Tetrahydroquinoline compositions as bet bromodomain inhibitors

ABSTRACT

The present invention relates to inhibitors of bromo and extra terminal (BET) bromodomains that are useful for the treatment of cancer, inflammatory diseases, diabetes, and obesity, having Formula I: 
     
       
         
         
             
             
         
       
     
     wherein W, X, Y, Z, R 1 , R 2 , R 5 , and R 8  are as described herein.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/546,775, filed Nov. 18, 2014, which claims the benefit of, andpriority to, U.S. Provisional Patent Application No. 61/905,639 filedNov. 18, 2013 and U.S. Provisional Patent Application No. 62/054,811filed Sep. 24, 2014. The entire contents of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention is directed to inhibitors of the bromo and extraterminal (BET) family of bromodomains useful in the treatment of diseaseor disorders associated with the modulation of the bromo and extraterminal (BET) family of bromodomains. Specifically, the invention isconcerned with compounds and compositions for inhibition of the bromoand extra terminal (BET) family of bromodomains, methods of treating,preventing, or ameliorating diseases or disorders associated with theinhibition of bromo and extra terminal (BET) family of bromodomains, andmethods of synthesis of these compounds.

BACKGROUND OF THE INVENTION

The bromo and extra terminal (BET) family proteins contain four membersin mammals, BRD2, BRD3, BRD4, and BRDT, with each of these containingtwo bromodomains (BRD): a conserved N-terminal bromodomain (bromodomain1 [BD1]) and a C-terminal bromodomain (bromodomain 2 [BD2]). BET familyproteins have been shown to have a critical role in cellularproliferation and cell cycle progression.

Bromodomain containing proteins are known to be involved intranscriptional regulation. In general, bromodomains are found inproteins that regulate chromatin structure and gene expression. Thepresence of these proteins is required for the systematic expression ofvarious growth and antiapoptotic genes. Additionally, these proteinsplay a role in the omnipresent cell cycle progression, as many nuclearproteins have bromodomains that interact with chromatin such as histoneacetyltransferases. Dysfunction of bromodomain containing proteins hasbeen linked to the development of a number of diseases, particularly tothe development of cancer. (Muller, S. Filippakopoulos, P. Knapp, S.(2011), Bromodomains as therapeutic targets. Expert Rev. Mol. Med. 13:e29). Bromodomains have also been implicated in inflammatory processes(Nicodeme et al, Nature, 2010, Vol. 468, pg. 1119).

BRD4 protein, as a gene product, contains 1362 amino acids. BRD4 BD1 is˜75-147; BRD4 BD2 is ˜368-440; thus each is 73 residues long. For thepurpose of biochemical screening, biophysics or X-ray crystallography,various protein constructs with additional N- and C-terminal residuesadded for both bromodomains are expressed and used. In addition, proteinconstructs with both bromodomains expressed within the same protein havealso been used (˜400 aa residues total).

The protein is comprised of four alpha helices, all left hand oriented,which is in stark contrast to the highly diverse sequential nature ofthe proteins. The helices (α_(Z), α_(A), α_(C), and α_(B)) are arrangedin such a way that the Z and A helices interact forming the long “ZAloop” and the C and B helices interact forming the short “BC loop.”(Dhalluin C., Carlson J. E., Zeng L., He C., Aggarwal A. K., Zhou M. M.(1999), Structure and ligand of a histone acetyltransferase bromodomain.Nature. 399, 491-6). These loops form hydrophobic pockets in the proteinwhere the protein interacts with acetylated lysine residues. Mutagenesisstudies suggest that tertiary contacts amongst the hydrophobic andaromatic residues between the two inter-helical loops contributedirectly to the structural stability of the protein. ((Dhalluin C.,Carlson J. E., Zeng L., He C., Aggarwal A. K., Zhou M. M. (1999),Structure and ligand of a histone acetyltransferase bromodomain. Nature.399, 491-6).

It has long been suggested that bromodomains play an important role onchromatin remodeling. In recent years, certain proteins of the doublebromodomain family, including BRD2, BRD3, BRD4, and BRDT have beenidentified as major epigenetic regulators in human cancer. As such,these double bromodomains appear to play a particularly vital role inhuman cancer proliferation and differentiation. For example, BRD4affects the breast cancer microenvironment and survival rates.(Crawford, N. P, Alsarraj, J., Lukes, L., Walker, R. C., Officewala, J.S., Yang, H. H., Lee, M. P., Ozato, K., Hunter, K. W. (2008),Bromodomain 4 Activation Predicts Breast Cancer Survival. Proc. Natl.Acad. Sci. USA. 105(17): 6380-6385). BRD4 also plays a role in Kaposi'ssarcoma and BRD2 factors in to some mixed lineage leukemias. (Guo, N.,Faller, D. V., Denis, G. V., Activation-Induced Nuclear Translocation ofRING3 (2001), J. Cell Sci. 113(17): 3085-3091). In addition, geneticknockdown by RNAi or exposure of cells to BET inhibitors has resulted insignificant transcriptional downregulation of MYC, a mutated version ofwhich is found in many cancers. (Delmore J. E., Issa G. C., Lemieux M.E., Rahl, P. B., Shi J., Jacobs H. M. (2011), BET Bromodomain Inhibitionas a Therapeutic Strategy to Target c-Myc. Cell. 146: 904-17). Thus,inhibition of these interactions and exposure of cells to BET inhibitorsresults in a significant transcriptional downregulation. This, in turn,provides the medical community with a novel pharmacological strategy forthe treatment of cancer.

The highly differentiated sequential nature of bromodomains has remaineda severe obstacle in the discovery of potent and efficacious bromodomaininhibitors. (Dawson, M. A, Prinjha, R. K., Dittman, A. Giotopoulos, G.Bantcheff, M., Chan, W-I., Robson, S. C., Chung, C., Hopf, C., Savitski,M. M., Hutmacher, C., Gudgin, E., Lugo, D., Beinke, S., Chapman. T. D.,Roberts, E. J., Soden. P. E., Auger, K. R., Mirguet, O., Doehner, K.,Delwel, R., Burnett, A. K., Jeffrey, P., Drewes, G., Lee, K., Huntly, B.J. P. and Kouzarides, T. (2011), Inhibition of BET recruitment ofchromatin as an effective treatment of MLL-fusion leukemia. Nature. 0:1-5; Picaud, S., Da Costa, D. Thanasopoulou, A., Filippakopoulos, P.,Fish, P., Philpott, M., Federov, O. Brennan, P., Bunnage, M. E., Owen,D. R., Bradner, J. E., Taniere, P., O'Sullivan, B., Muller, S,Schwaller, J., Stankovic, T., Knapp, S., PFI-1—A highly SelectiveProtein Interaction Inhibitor Targeting BET Bromodomains, Cancer Res.,73(11), 2013, 3336-3346). As a result, there are currently no approvedbromodomain inhibitors available on the market despite theirwell-recognized potential as anti-cancer therapeutic agents. For thesereasons, there remains a considerable need for novel and potent smallmolecule modulators of BET bromodomains.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to compounds of Formula I:

and pharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, and tautomers thereof,

wherein:

W is O, S, C(O), or CHR³;

X is N or CR⁴;

Y is N or CR⁶;

Z is N or CR⁷;

R¹ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

R² is hydrogen or NR^(a)R^(b);

R³ is hydrogen, halogen, hydroxyl, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

R⁴ is hydrogen, —(CH₂)_(n)R^(d), —O(CH₂)_(n)R^(d), —N(CH₂)_(n)R^(d),—O(CH₂)_(n)C(O)R^(d), or —O(CH₂)_(n)S(O)₂R^(d);

R⁵ and R⁶ are each independently hydrogen, halogen, cyano, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—(C₁-C₆)-alkylene-aryl, —(C₁-C₆)-alkylene-heteroaryl,—(C₁-C₆)-alkylene-heterocycloalkyl, —(CR^(a)R^(b))_(n)OR^(c),—(CR^(a)R^(b))_(n)R^(c), —O(CR^(a)R^(b))_(n)NR^(a)R^(b), —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)S(O)₂R^(b), or R^(c), wherein said alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, and heteroaryl are optionally substituted withone or more substituents independently selected from R^(a), R^(b), andR^(c);

R⁷ is hydrogen or halogen;

R⁸ is R^(a), —OR^(a), —NR^(a), or heterocycloalkyl;

R^(a) and R^(b) are each independently hydrogen, halogen, C₁-C₆ alkyl,cycloalkyl, or heterocycloalkyl, wherein C₁-C₆ alkyl, cycloalkyl, orheterocycloalkyl is optionally substituted with one or more Re;

R^(c) is —NH₂, OH, —NH(C₁-C₆ alkyl), —O(CH₂)_(n)NR^(a)R^(b), —NH(C₁-C₆alkoxy), —(CH₂)_(n)R^(a), —(CH₂)_(n)OR^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —(CH₂)_(n)S(O)₂CH₃, —S(O)₂R^(a), —S(O)₂NR^(a)R^(b),—NR^(a)—S(O)₂R^(b), —NHC(O)R^(a), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo, whereinC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkoxy, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R^(e);

or two adjacent R^(c) can combine with the carbons to which they areattached to form a carbocycle or heterocycle;

R^(d) is hydrogen, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein saidalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected fromR^(a), R^(b), and R^(c);

R^(e) is hydrogen, halogen, OH, C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, oxo, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkoxy,or S(O)₂(C₁-C₆ alkyl); and

n is 0, 1, or 2.

Another aspect of the present invention relates to a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt, enantiomer, hydrate, solvate, prodrug, isomer, ortautomer thereof and a pharmaceutically acceptable carrier.

In another aspect, the present invention relates to a method ofmodulating one or more of BET-family bromodomains. The method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptablesalt, enantiomer, hydrate, solvate, prodrug, isomer, or tautomerthereof.

Another aspect of the present invention relates to a method ofinhibiting one or more of BET-family bromodomains. The method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptablesalt, enantiomer, hydrate, solvate, prodrug, isomer, or tautomerthereof.

In another aspect, the present invention relates to a method ofinhibiting one or more of BET-family bromodomains. The method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a pharmaceutical composition of Formula I.

Another aspect of the present invention relates to a method of treating,preventing, inhibiting, or eliminating a disease or disorder in apatient associated with the inhibition of one or more of BET-familybromodomains. The method comprises administering to a patient in needthereof a therapeutically effective amount of a compound of Formula Iherein described, wherein the disease or disorder is selected from thegroup consisting of cancer, inflammatory disorders, irritable bowelsyndrome, inflammatory bowel disease, rheumatoid arthritis, obesity anddiabetes.

In another aspect, the present invention relates to a male contraceptivecomprising a therapeutically effective amount of a compound of Formula Iherein described.

The present invention provides inhibitors of BET domains that aretherapeutic agents in the treatment of diseases such as cancer,inflammation, metabolic and neurological disorders, and infectiousdiseases.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds and compositions that arecapable of modulating the activity the BET family bromodomains, e.g.,BRD2, BRD3, BRD4, and BRDT bromodomains. The invention features methodsof treating, preventing or amerliorating a disease or disorderassociated with BET bromodomains by administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I),(II), (III), or (IV), or a pharmaceutically acceptable salt, enantiomer,hydrate, solvate, prodrug, isomer, or tautomer thereof. The methods ofthe present invention can be used in the treatment of a variety of BETbromodomain dependent diseases and disorders by inhibiting the activityof a BET bromodomains. Inhibition of BET bromodomains provides a novelapproach to the treatment, prevention, or amelioration of diseasesincluding, but not limited to, cancer, inflammatory diseases, diabetesand obesity, and developing male contraceptives.

One aspect of the present invention relates to compounds of Formula I

and pharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, or tautomers thereof, wherein W, X, Y, Z, R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R^(a), R^(b), R^(c), R^(d), R^(e) and n are asdescribed above.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

DEFINITIONS

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings. If a definition is missing, the conventional definition asknown to one skilled in the art controls.

As used herein, the terms “including,” “containing,” and “comprising”are used in their open, non-limiting sense.

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently

A “patient” is a mammal, e.g., a human, mouse, rat, guinea pig, dog,cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus. “Patient” includes both human and animals.

The term “inhibitor” refers to a molecule such as a compound, a drug,enzyme, or a hormone that blocks or otherwise interferes with aparticular biologic activity.

The term “bromodomain inhibitor” denotes a compound which inhibitsbinding of a bromodomain with its cognate acetylated proteins. In oneembodiment the bromodomain inhibitor is a compound which inhibits thebinding of any one or a combination of bromodomains to acetylated lysineresidues. In a further embodiment the bromodomain inhibitor is acompound which inhibits the binding of a bromodomain to acetylatedlysine residues on histones, particularly histones H3 and H4.

The term “BET family bromodomain inhibitor” or “inhibitor of bromodomainof the BET family proteins” means a compound that inhibits binding ofBET (bromo and extra terminal) bromodomains BRD2 BD1, BRD2 BD2, BRD3BD1, BRD3 BD2, BRD4 BD1, BRD4 BD2, BRDT BD1, or BRDT BD2. In oneembodiment BET family bromodomain inhibitors are compounds according toFormulas I-IV. According to another embodiment, BET family bromodomaininhibitors are compounds selected from Table 1.

The terms “effective amount” or “therapeutically effective amount” whenused in connection with a compound refer to a sufficient amount of thecompound to provide the desired biological result. That result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic use is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in a disease. An appropriate“effective amount” in any individual case may be determined by one ofordinary skill in the art using routine experimentation. Thus, theexpression “effective amount” generally refers to the quantity for whichthe active substance has therapeutic effects. In the present case theactive substance is the inhibitor of the bromodomains of the BETproteins.

As used herein, the terms “treat” or “treatment” are synonymous with theterm “prevent” and are meant to indicate a postponement of developmentof diseases, preventing the development of diseases, and/or reducingseverity of such symptoms that will or are expected to develop. Thus,these terms include ameliorating existing disease symptoms, preventingadditional symptoms, ameliorating or preventing the underlying causes ofsymptoms, inhibiting the disorder or disease, e.g., arresting thedevelopment of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping or alleviatingthe symptoms of the disease or disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

By using the terms “pharmaceutically acceptable” or “pharmacologicallyacceptable” it is intended to mean a material which is not biologically,or otherwise, undesirable—the material may be administered to anindividual without causing any substantially undesirable biologicaleffects or interacting in a deleterious manner with any of thecomponents of the composition in which it is contained.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject. Excipients should beselected on the basis of compatibility and the release profileproperties of the desired dosage form. Exemplary carrier materialsinclude, e.g., binders, suspending agents, disintegration agents,filling agents, surfactants, solubilizers, stabilizers, lubricants,wetting agents, diluents, and the like.

“Pharmaceutically compatible carrier materials” may comprise, e.g.,acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate,calcium lactate, maltodextrin, glycerine, magnesium silicate, sodiumcaseinate, soy lecithin, sodium chloride, tricalcium phosphate,dipotassium phosphate, sodium stearoyl lactylate, carrageenan,monoglyceride, diglyceride, pregelatinized starch, and the like. See,e.g., Hoover, John E., Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa. 1975.

As used herein, the term “subject” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theclass Mammalia: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the presentinvention, the mammal is a human.

The present invention also includes “prodrugs” of compounds of theinvention. The term “prodrug” means a compound which is convertible invivo by metabolic means (e.g., by hydrolysis) to a disclosed compound oractive ingredient. Prodrugs can be prepared by techniques known to oneskilled in the art. These techniques generally modify appropriatefunctional, e.g., a hydroxy, amino, carboxylic, etc., groups in a givencompound. These modified functional groups, however, regenerate originalfunctional groups by routine manipulation or in vivo. Examples ofprodrugs include, but are not limited to esters (e.g., acetate, formate,and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl)of hydroxy or amino functional groups in compounds of the invention,amides (e.g., trifluoroacetylamino, acetylamino, and the like), and thelike. Since prodrugs are known to enhance numerous desirable qualitiesof pharmaceuticals (e.g., solubility, bioavailability, manufacturing,transport, pharmacodynamics, etc.), the compounds of the presentinvention may be delivered in prodrug form. Prodrugs, for instance, maybe bioavailable by oral administration even when the parent drug is not.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same, andcompositions containing the same. Generally speaking, prodrugs arederivatives of per se drugs that after administration undergo conversionor metabolism to the physiologically active species. The conversion maybe spontaneous, such as hydrolysis in the physiological environment, ormay be enzyme-catalyzed. Prodrugs include compounds that can beoxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated,hydrolyzed, esterified, alkylated, dealkylated, acylated, deacylated,phosphorylated, and/or dephosphorylated to produce the active compound.

The term “IC₅₀”, as used herein, refers to concentrations at which ameasurable activity, phenotype or response, for example growth orproliferation of cells such as tumor cells, is inhibited by 50%. IC₅₀values can be estimated from an appropriate dose-response curve, forexample by eye or by using appropriate curve fitting or statisticalsoftware. More accurately, IC₅₀ values may be determined usingnon-linear regression analysis.

The terms “administered”, “administration”, or “administering” as usedin this disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body, including ananimal, in need of treatment by bringing such individual in contactwith, or otherwise exposing such individual to, such compound.

As used herein, “alkyl” means a straight chain or branched saturatedchain having from 1 to 10 carbon atoms. Representative saturated alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like,and longer alkyl groups, such as heptyl, and octyl and the like. Analkyl group can be unsubstituted or substituted. Alkyl groups containingthree or more carbon atoms may be straight, or branched. As used herein,“lower alkyl” means an alkyl having from 1 to 6 carbon atoms.

As used herein, an “alkenyl” includes an unbranched or branchedhydrocarbon chain containing 2-12 carbon atoms. The “alkenyl” groupcontains at least one double bond. The double bond of an alkenyl groupcan be unconjugated or conjugated to another unsaturated group. Examplesof alkenyl groups include, but are not limited to, ethylenyl, vinyl,allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl,2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl andthe like. An alkenyl group can be unsubstituted or substituted. Alkenyl,as defined herein, may also be branched or straight.

As used herein, “alkynyl” includes an unbranched or branched unsaturatedhydrocarbon chain containing 2-12 carbon atoms. The “alkynyl” groupcontains at least one triple bond. The triple bond of an alkynyl groupcan be unconjugated or conjugated to another unsaturated group. Examplesof alkynyl groups include, but are not limited to, ethynyl, propynyl,butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl,4-propyl-2-pentynyl, 4-butyl-2-hexynyl and the like. An alkynyl groupcan be unsubstituted or substituted.

The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical.Any of the above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. As defined herein,an alkylene may also be a C₁-C₆ alkylene. An alkylene may further be aC₁-C₄alkylene. Typical alkylene groups include, but are not limited to,—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

The terms “trifluoromethyl”, “sulfonyl”, and “carboxyl” refers to CF₃,S(O)₂, and C(O)OH, respectively.

The term “hydroxyl” or “hydroxy” means an OH group;

The term “hydroxyalkyl” means an alkyl group as defined above, where thealkyl group is substituted with one or more OH groups. Examples ofhydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “alkoxy” as used herein refers to a straight or branched chainsaturated hydrocarbon containing 1-12 carbon atoms containing a terminal“O” in the chain, i.e., —O(alkyl). Examples of alkoxy groups include,without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, orpentoxy groups.

“Aralkyl” or “arylalkyl” means an a C₁-C₆ alkyl group, as defined hereinabove, substituted with an aryl ring containing from 3 to 24 ring atomsper ring. For example, arylalkyl groups herein described can have thefollowing formula

where n is an integer from 1 to 6. Non-limiting examples of suitablearalkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. Thebond to the parent moiety is through the alkyl.

“Cycloalkylalkyl” means monocyclic saturated carbon rings containing3-18 carbon atoms further substituted with C₁-C₆ alkyl groups. Ingeneral cycloalkylalkyl groups herein described display the followingformula

where m is an integer from 1 to 6 and n is an integer from 1 to 16.

“Heterocycloalkyl-alkyl” means an a C₁-C₆ alkyl group, as defined hereinabove, substituted with an heterocycloalkyl ring containing from 3 to 24ring atoms per ring. For example, an heterocycloalkyl-alkyl group canhave the following structure

where n is an integer from 1 to 6. The bond to the parent moiety isthrough the alkyl.

“Heteroaryl alkyl” means an a C₁-C₆ alkyl group, as defined hereinabove, substituted with a heteroaryl ring containing from 5 to 24 ringatoms per ring. For example, a heteroarylalkyl group can have thefollowing structure

where n is an integer from 1 to 6. The bond to the parent moiety isthrough the alkyl.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

As used herein, references to hydrogen may also refer to a deuteriumsubstitution if desired. The term “deuterium” as used herein means astable isotope of hydrogen having odd numbers of protons and neutrons.

The term “halo” or “halogen” refers to fluorine, chlorine, bromine, oriodine.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, which is substituted one or more halogen. Examples of haloalkylgroups include, but are not limited to, trifluoromethyl, difluoromethyl,pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, asdefined herein, which is substituted one or more halogen. Examples ofhaloalkyl groups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond, i.e.,

The term “amine” as used herein refers to primary (R—NH₂, R≠H),secondary (R₂—NH, R₂≠H) and tertiary (R₃—N, R≠H) amines. A substitutedamine is intended to mean an amine where at least one of the hydrogenatoms has been replaced by the substituent.

The term “amino” as used herein means a substituent containing at leastone nitrogen atom. Specifically, NH₂, —NH(alkyl) or alkylamino,—N(alkyl)₂ or dialkylamino, amide-, carbamide-, urea, and sulfamidesubstituents are included in the term “amino”.

The term “(amino)alkoxy” or “aminoalkoxy” as used herein means an alkoxygroup, as defined herein above, where the straight or branched chainsaturated hydrocarbon of the alkoxy is substituted with one or moreamino groups.

The term “aminoalkyl” or “amino(alkyl)” as used herein refers to analkyl group, as defined herein, which is substituted one or more timeswith one or more amino groups.

The term “alkylamino” as used herein refers to an amino or NH2 groupwhere one of the hydrogens has been replaced with an alkyl group, asdefined herein above, i.e., —NH-alkyl. Example of alkylamino groupsinclude, but are not limited to, methylamino (i.e., —NHCH₃), ethylamino,propylamino, iso-propylamino, n-butylamino, sec-butylamino, andtert-butylamino.

The term “dialkylamino” as used herein refers to an amino or NH₂ groupwhere both of the hydrogens have been replaced with alkyl groups, asdefined herein above, i.e., —N(alkyl)₂. The alkyl groups on the aminogroup can be the same ore different alkyl groups. Example of alkylaminogroups include, but are not limited to, dimethylamino (i.e., —N(CH₃)₂),diethylamino, dipropylamino, diiso-propylamino, di-n-butylamino,di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino,methyl(butylamino), etc.

The term “aryloxy” refers to an aryl ring as defined herein containing aterminal “O”, i.e., Ar—O—, where Ar is aryl. Examples of aryloxy groupsinclude, without limitation, phenoxy, biphenoxy, and naphtyloxy.

The term “methylenedioxy” as used herein means a functional group withthe structural formula —O—CH₂—O— which is connected to the molecule bytwo chemical bonds via the oxygens.

As used herein, “alkoxyalkyl” means an alkyl group as defined hereinfurther substituted with one or more alkoxy groups as defined herein,i.e., alkyl-O-alkyl-.

The term “(alkoxyalkyl)amino” as used herein means an amino groupsubstituent having at least one alkoxyalkyl group as defined above andat least one amino group as defined above.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 3 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. The substituents can themselves be optionally substituted.Furthermore when containing two fused rings the aryl groups hereindefined may have an unsaturated or partially saturated ring fused with afully saturated ring. Exemplary ring systems of these aryl groupsinclude, but are not limited to, phenyl, biphenyl, naphthyl,anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl,tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 18 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. The substituents can themselves be optionallysubstituted. Examples include, but are not limited to, benzothiophene,furyl, thienyl, pyrrolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl,pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl,indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl,thiadiazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, benzoimidazolyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1□²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl,benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings theheteroaryl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated, monocyclic, fused or spiro polycyclic, carbocycle having from3 to 18 carbon atoms per ring. The cycloalkyl ring or carbocycle may beoptionally substituted by one or more substituents, e.g., 1 to 5substituents, at any point of attachment. The substituents canthemselves be optionally substituted. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, decahydronaphthalenyl,octahydro-1H-indenyl, cyclopentenyl, cyclohexenyl, cyclohexa-1,4-dienyl,cyclohexa-1,3-dienyl, 1,2,3,4-tetrahydronaphthalenyl,octahydropentalenyl, 3a,4,5,6,7,7a-hexahydro-1H-indenyl,1,2,3,3a-tetrahydropentalenyl, bicyclo[3.1.0]hexanyl,bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl,6-methylbicyclo[3.1.1]heptanyl, 2,6,6-trimethylbicyclo[3.1.1]heptanyl,and derivatives thereof.

As used herein, the term “heterocycloalkyl” refers to a saturated orpartially saturated monocyclic, or fused or spiro, polycyclic, ringstructure containing carbon and heteroatoms taken from oxygen, nitrogen,or sulfur and wherein there is not delocalized 7-electrons (aromaticity)shared among the ring carbon or heteroatoms. The heterocycloalkyl ringstructure may be substituted by one or more substituents. Thesubstituents can themselves be optionally substituted. Examples ofheterocyclyl rings include, but are not limited to, oxetanyl,azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl,thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl,dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinylS-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl,diazepinyl, tropanyl, homotropanyl, dihydrothiophen-2(3H)-onyl,tetrahydrothiophene 1,1-dioxide, 2,5-dihydro-1H-pyrrolyl,imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one,1,3-dioxolan-2-one, isothiazolidine 1,1-dioxide,4,5-dihydro-1H-imidazolyl, 4,5-dihydrooxazolyl, oxiranyl, pyrazolidinyl,4H-1,4-thiazinyl, thiomorpholinyl, 1,2,3,4-tetrahydropyridinyl,1,2,3,4-tetrahydropyrazinyl, 1,3-oxazinan-2-one, tetrahydro-2H-thiopyran1,1-dioxide, 7-oxabicyclo[2.2.1]heptanyl, 1,2-thiazepane 1,1-dioxide,octahydro-2H-quinolizinyl, 1,3-diazabicyclo[2.2.2]octanyl,2,3-dihydrobenzo[b][1,4]dioxine, 3-azabicyclo[3.2.1]octanyl,8-azaspiro[4.5]decane, 8-oxa-3-azabicyclo[3.2.1]octanyl,2-azabicyclo[2.2.1]heptane, 2,8-diazaspiro[5.5]undecanyl,2-azaspiro[5.5]undecanyl, 3-azaspiro[5.5]undecanyl,decahydroisoquinolinyl, 1-oxa-8-azaspiro[4.5]decanyl,8-azabicyclo[3.2.1]octanyl, 1,4′-bipiperidinyl, azepanyl,8-oxa-3-azabicyclo[3.2.1]octanyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, 1,4-diazepanyl,phenoxathiinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzo[b][1,4]dioxinyl, 4-(piperidin-4-yl)morpholinyl,3-azaspiro[5.5]undecanyl, decahydroquinolinyl, piperazin-2-one,1-(pyrrolidin-2-ylmethyl)pyrrolidinyl, 1,3′-bipyrrolidinyl, and6,7,8,9-tetrahydro-1H,5H-pyrazolo[1,2-a][1,2]diazepinyl.

Numerical ranges, as used herein, are intended to include sequentialintegers. For example, a range expressed as “from 0 to 4” would include0, 1, 2, 3 and 4.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents wherein the substituentsmay connect to the specified group or moiety at one or more positions.For example, an aryl substituted with a cycloalkyl may indicate that thecycloalkyl connects to one atom of the aryl with a bond or by fusingwith the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified groupbears no substituents.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, oxo, -halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —OC₁-C₆ alkenyl, —OC₁-C₆ alkynyl,—C₁-C₆ alkenyl, —C₁-C₆ alkynyl, —OH, CN (cyano), —CH₂CN, —OP(O)(OH)₂,—C(O)OH, —OC(O)C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —C(O)—C₀-C₆alkylenyl-cycloalkyl, —C(O)—C₀-C₆ alkylenyl-heterocycloalkyl,—C(O)—C₀-C₆ alkylenyl-aryl, —C(O)—C₀-C₆ alkylenyl-heteroaryl,—OC(O)OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)NH cycloalkyl,—C(O)N(C₁-C₆ alkyl)cycloalkyl, —C(O)NHheterocycloalkyl, —C(O)N(C₁-C₆alkyl)heterocycloalkyl, —C(O)NHaryl, —C(O)N(C₁-C₆ alkyl)aryl,—C(O)NHheteroaryl, —C(O)N(C₁-C₆ alkyl)heteroaryl, —S(O)₂—C₁-C₆ alkyl,—S(O)₂—C₁-C₆ haloalkyl, —S(O)₂— cycloalkyl, —S(O)₂-heterocycloalkyl,—S(O)₂— aryl, —S(O)₂-heteroaryl —C₀-C₆ alkylenyl-S(O)₂NH₂, —S(O)₂NHC₁-C₆alkyl, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NHcycloalkyl,—S(O)₂NHheterocycloalkyl, —S(O)₂NHaryl, —S(O)₂NHhetereoaryl,—NHS(O)₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂(C₁-C₆ alkyl), —NHS(O)₂aryl,—N(C₁-C₆ alkyl)S(O)₂ aryl, —NHS(O)₂ heteroaryl, —N(C₁-C₆ alkyl)S(O)₂heteroaryl, —NHS(O)₂ cycloalkyl, —N(C₁-C₆ alkyl)S(O)₂ cycloalkyl,—NHS(O)₂ heterocycloalkyl, —N(C₁-C₆ alkyl)S(O)₂ heterocycloalkyl,—N(C₁-C₆ alkyl)S(O)₂ aryl, —C₀-C₆ alkylenyl-aryl, —C₀-C₆alkylenyl-heteroaryl, —C₀-C₆ alkylenyl-cycloalkyl, —C₀-C₆alkylenyl-heterocycloalkyl, —O-aryl, —NH-aryl, and N(C₁-C₆ alkyl)aryl.The substituents can themselves be optionally substituted. When amultifunctional moiety is shown, the point of attachment to the core isindicated by a line, e.g., (cycloalkyloxy)alkyl-refers to alkyl beingthe point of attachment to the core while cycloalkyl is attached toalkyl via the oxy group. “Optionally substituted” also refers to“substituted” or “unsubstituted”, with the meanings described above.

The term “oxy” as used herein refers to an “—O—” group.

The term “oxo” as used herein refers to an “═O” group.

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I), (II), (III), or(IV) may have one or more asymmetric carbon atoms and may occur asracemates, racemic mixtures and as individual enantiomers ordiastereomers.

The term “salt(s)”, as employed herein, denotes acidic salts formed withinorganic and/or organic acids, as well as basic salts formed withinorganic and/or organic bases. In addition, when a compound of theFormula contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula may be formed, for example, by reacting a compound ofFormula with an amount of acid or base, such as an equivalent amount, ina medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

In another embodiment of the invention, the compounds of Formulae(I)-(IV) are enantiomers. In some embodiments the compounds are the(S)-enantiomer. In other embodiments the compounds are the(R)-enantiomer. In yet other embodiments, the compounds of Formula (I),(II), (III), or (IV) may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Compounds of the various Formulae, and salts, solvates, esters andprodrugs thereof, may exist in their tautomeric form (for example, as anamide or imino ether). All such tautomeric forms are contemplated hereinas part of the present invention.

The compounds of the various Formulae may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of the variousFormulae as well as mixtures thereof, including racemic mixtures, formpart of the present invention. In addition, the present inventionembraces all geometric and positional isomers. For example, if acompound of the various Formulae incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Each compound herein disclosedincludes all the enantiomers that conform to the general structure ofthe compound. The compounds may be in a racemic or enantiomerically pureform, or any other form in terms of stereochemistry. The assay resultsmay reflect the data collected for the racemic form, theenantiomerically pure form, or any other form in terms ofstereochemistry.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the various Formulae may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the various Formulae may existin different tautomeric forms, and all such forms are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of the various Formulae incorporates a double bond or afused ring, both the cis- and trans-forms, as well as mixtures, areembraced within the scope of the invention. Also, for example, allketo-enol and imine-enamine forms of the compounds are included in theinvention.) Individual stereoisomers of the compounds of the inventionmay, for example, be substantially free of other isomers, or may beadmixed, for example, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H (or D),³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of the various Formulae (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and/or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of the various Formulaecan generally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples herein below, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

The compounds of Formulae I to IV may form salts which are also withinthe scope of this invention. Reference to a compound of the Formulaherein is understood to include reference to salts thereof, unlessotherwise indicated.

The present invention relates to compounds which are modulators of oneor more bromodomains of the BET family. In one embodiment, the compoundsof the present invention are inhibitors of one or more bromodomains ofthe BET family.

The invention is directed to compounds as described herein andpharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, or tautomers thereof, and pharmaceutical compositionscomprising one or more compounds as described herein, orpharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, or tautomers thereof.

Compounds of the Invention

The present invention relates to compounds, or pharmaceuticallyacceptable salts or isomers thereof, capable of modulating BET familybromodomains, including BRD2, BRD3, BRD4 and BRDT, which are useful forthe treatment of diseases and disorders associated with modulation ofBET family bromodomains. The invention further relates to compounds, orpharmaceutically acceptable salts or isomers thereof, which are usefulfor inhibiting BET family bromodomains.

Another aspect of the present invention is the provision ofpharmaceutical compositions comprising therapeutically effective amountsof at least one compound of Formula I, II, III, or IV.

One aspect of the present invention relates to compounds of Formula I

and pharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, and tautomers thereof, wherein W, X, Y, Z, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(a), R^(b), R^(c), R^(d), and n are asdescribed above.

One embodiment of the invention relates to compounds of Formula II

and pharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, and tautomers thereof,

wherein:

W is O, C(O), or CHR³;

Ar is aryl or heteroaryl;

R² is hydrogen or NR^(a)R^(b);

R³ is hydrogen, hydroxy, or halo;

R⁴ hydrogen, —O(CH₂)_(n)R^(d), —O(CH₂)_(n)C(O)R^(d),—O(CH₂)_(n)S(O)₂R^(d) or —N(CH₂)_(n)R^(d);

R⁷ is hydrogen or halo;

R⁸ is R^(a), —OR^(a), or heterocycloalkyl;

R^(a) and R^(b) are each independently hydrogen, C₁-C₆ alkyl,cycloalkyl, or heterocycloalkyl;

R^(c) is R^(a), —(CH₂)_(n)OR^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b)—S(O)₂R^(a), halo, or oxo; and

n is 0, 1, or 2.

R^(d) is hydrogen, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected fromR^(a), R^(b), and R^(c);

and n is 0, 1, or 2.

Another embodiment of the invention relates to compounds of Formula III

and pharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, and tautomers thereof,

wherein:

Ar is pyrazolyl or phenyl;

R⁴ is hydrogen, —O(CH₂)_(n)R^(d), —O(CH₂)_(n)C(O)R^(d), or—O(CH₂)_(n)S(O)₂R^(d);

R⁸ is methyl, methoxy, or cyclopropyl;

R^(a) and R^(b) are each independently hydrogen or C₁-C₆ alkyl;

R^(c) is —(CH₂)_(n)R^(a), —(CH₂)_(n)OR^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —(CH₂)_(n)S(O)₂CH₃, —S(O)₂R^(a), —S(O)₂NR^(a)R^(b),C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, cycloalkyl, heterocycloalkyl, halo,cyano, or oxo;

R^(d) is hydrogen, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected fromR^(a), R^(b), and R^(c); and n is 0, 1, or 2.

Another embodiment of the invention relates to compounds of Formula IV

and pharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, and tautomers thereof,

wherein:

R⁴ is —O(CH₂)_(n)R^(d), —O(CH₂)_(n)C(O)R^(d), or —O(CH₂)_(n)S(O)₂R^(d);

R⁸ is alkyl, cycloalkyl, O-alkyl, or O-cycloalkyl

R^(a) and R^(b) are each independently hydrogen or C₁-C₆ alkyl;

R^(c) is —(CH₂)_(n)R^(a), —(CH₂)_(n)OR^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b)—S(O)₂R^(a), —S(O)₂NR^(a)R^(b), C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano,or oxo;

R^(d) is hydrogen, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected fromR^(a), R^(b), and R^(c); and

n is 0, 1, or 2.

An aspect of the present invention concerns compounds which are, or canbe, inhibitors of one or more bromodomains of the BET family.

An aspect of the present invention concerns the use of an inhibitor ofBET family bromodomains for the preparation of a medicament used in thetreatment, prevention, inhibition or elimination of tumors.

An aspect of the present invention concerns the use of an inhibitor ofBET family bromodomains for the preparation of a medicament used in thetreatment, prevention, inhibition or elimination of cancer.

An aspect of the present invention concerns the use of an inhibitor ofBET family bromodomains for the preparation of a medicament used intreatment, prevention, inhibition or elimination of diseases associatedwith chronic autoimmune and inflammatory conditions.

An aspect of the present invention concerns the use of an inhibitor ofBET family bromodomains for the preparation of a medicament used intreatment, prevention, inhibition or elimination of diseases associatedwith acute inflammatory conditions.

An aspect of the present invention concerns the use of an inhibitor ofBET family bromodomains for the preparation of a medicament used intreatment, prevention, inhibition or elimination of diseases associatedwith systemic inflammatory response syndrome.

An aspect of the present invention concerns the use of an inhibitor ofBET family bromodomains for the preparation of a medicament used intreatment, prevention, inhibition or elimination of diseases ordisorders associated with virus, bacterial or fungal infections.

An aspect of the present invention concerns the use of an inhibitor ofBET family bromodomains for the preparation of a medicament used intreatment, prevention, inhibition or elimination of diabetes or obesity.

An aspect of the present invention concerns the use of an inhibitor ofBET family bromodomains for the preparation of a male contraceptive.

One embodiment of the present invention relates to compounds of FormulaI, wherein X is CR⁴ and Y and Z are CH.

Another embodiment of the present invention relates to compounds ofFormula I, wherein W is CHR³.

Another embodiment of the present invention relates to compounds ofFormula II, wherein W is CHR³.

Another embodiment of the present invention relates to compounds ofFormula II, wherein Ar is pyrazole or phenyl.

Another embodiment of the present invention relates to compounds ofFormula III, wherein Ar is pyrazole and R^(c) is cycloalkyl orheterocycloalkyl.

Another aspect of the present invention relates to compounds of FormulaIII, wherein R^(c) is cyclopropyl.

Yet another embodiment of the present invention is directed to compoundsof Formula III, wherein Ar is phenyl, R^(c) is —(CH₂)_(n)S(O)₂CH₃.

Another embodiment of the present invention is directed to compounds ofFormula IV, wherein R^(c) is cycloalkyl, or heterocycloalkyl.

Another embodiment of the present invention is directed to compounds ofFormula IV, wherein R⁴ is —O(CH₂)_(n)R^(c).

Another embodiment of the present invention is directed to compounds ofFormula IV, wherein R^(c) is aryl, heteroaryl, or cycloalkyl.

In some embodiments of the present invention, W is CH. In anotherembodiment, W is CH. In yet another embodiment, W is CH and X is CR₄. Inanother embodiment, W is CH, X is CR₄ and Y is CH. In yet anotherembodiment, W is CH, X is CR₄, Y is CH, and Z is CR⁷. In anotherembodiment, W is CH, X is CR₄, Y is CH, Z is CR⁷, and R¹ is C₁-C₆ alkyl.In another embodiment, W is CH, X is CR₄, Y is CH, Z is CR⁷, R¹ is C₁-C₆alkyl and R² is H. In yet another embodiment, W is CH, X is CR₄, Y isCH, Z is CR⁷, R¹ is C₁-C₆ alkyl, R² is H, and R⁸ is R^(a) or OR^(a). Inanother embodiment, W is CH, X is CR₄, Y is CH, Z is CR⁷, R¹ is C₁-C₆alkyl, R² is H, R⁸ is R^(a) or OR^(a), and R^(a) is C₁-C₆ alkyl orcycloalkyl. In yet another embodiment, W is CH, X is CR₄, Y is CH, Z isCR⁷, R¹ is C₁-C₆ alkyl, R² is H, R⁸ is R^(a) or OR^(a), R^(a) is C₁-C₆alkyl or cycloalkyl, and R⁴ is OR^(d). In another embodiment, W is CH, Xis CR₄, Y is CH, Z is CR⁷, R¹ is C₁-C₆ alkyl, R² is H, R⁸ is R^(a) orOR^(a), R^(a) is C₁-C₆ alkyl or cycloalkyl, R⁴ is OR^(d), and R^(d) isC₁-C₆ alkyl, C₁-C₆ haloalkyl, cycloalkyl, aryl, or heteroaryl optionallysubstituted with one or more preferred substituents. In yet anotherembodiment, W is CH, X is CR₄, Y is CH, Z is CR⁷, R¹ is C₁-C₆ alkyl, R²is H, R⁸ is R^(a) or OR^(a), R^(a) is C₁-C₆ alkyl or cycloalkyl, R⁴ isOR^(d), R^(d) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, cycloalkyl, aryl, orheteroaryl optionally substituted with one or more preferredsubstituents, and R⁵ is heteroaryl optionally substituted with one ormore preferred substituents.

In some embodiments of the present invention, W is CH. In anotherembodiment, W is CH. In yet another embodiment, W is CH and X is CR₄. Inanother embodiment, W is CH, X is CR₄ and Y is CH. In yet anotherembodiment, W is CH, X is CR₄, Y is CH, and Z is CH or CF. In anotherembodiment, W is CH, X is CR₄, Y is CH, Z is CH or CF, and R¹ is methyl.In another embodiment, W is CH, X is CR₄, Y is CH, Z is CH or CF, R¹ ismethyl and R² is H. In yet another embodiment, W is CH, X is CR₄, Y isCH, Z is CH or CF, R¹ is methyl, R² is H, and R⁸ is R^(a) or OR^(a). Inanother embodiment, W is CH, X is CR₄, Y is CH, Z is CH or CF, R¹ ismethyl, R² is H, R⁸ is R^(a) or OR^(a), and R^(a) is C₁-C₆ alkyl orcycloalkyl. In yet another embodiment, W is CH, X is CR₄, Y is CH, Z isCH or CF, R¹ is methyl, R² is H, R⁸ is R^(a) or OR^(a), R^(a) is C₁-C₆alkyl or cycloalkyl, and R⁴ is OR^(d). In another embodiment, W is CH, Xis CR₄, Y is CH, Z is CH or CF, R¹ is methyl, R² is H, R⁸ is R^(a) orOR^(a), R^(a) is C₁-C₆ alkyl or cycloalkyl, R⁴ is OR^(d), and R^(d) isC₁-C₆ alkyl, C₁-C₆ haloalkyl, cycloalkyl, aryl, or heteroaryl optionallysubstituted with one or more preferred substituents. In yet anotherembodiment, W is CH, X is CR₄, Y is CH, Z is CH or CF, R¹ is methyl, R²is H, R⁸ is R^(a) or OR^(a), R^(a) is C₁-C₆ alkyl or cycloalkyl, R⁴ isOR^(d), R^(d) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, cycloalkyl, aryl, orheteroaryl optionally substituted with one or more preferredsubstituents, and R⁵ is heteroaryl optionally substituted with one ormore preferred substituents.

Another aspect of the present invention is a pharmaceutical compositioncomprising the compound of Formula I and a pharmaceutically acceptablecarrier.

Another aspect of the present invention is a pharmaceutical compositioncomprising the compound of Formula I and a pharmaceutically acceptablecarrier comprising therapeutically effective amounts of one or moreadditional therapeutic agents.

In some embodiment the present invention relates to a pharmaceuticalcomposition comprising the compound of Formula I and a pharmaceuticallyacceptable carrier comprising therapeutically effective amounts of oneor more additional therapeutic agents, wherein said additionaltherapeutic agents are selected from the group consisting of cytotoxicagent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan,camptostar, topotecan, paclitaxel, docetaxel, the epothilones,tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide,SCH 66336, tipifarnib, R115777, L778,123, BMS 214662, C225, GLEEVEC®,Intron®, Peg-Intron®, aromatase combinations, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, leucovirin, oxaliplatin(ELOXATIN®), Pentostatine, Vinblastine, Vincristine, Vindesine,Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin,Mithramycin™, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Rituximab, C225, Campath, leucovorin, dexamethasone, bicalutamide,carboplatin, chlorambucil, cisplatin, letrozole, megestrol, andvalrubicin.

Another aspect of the present invention is directed to a method ofinhibiting one or more of BET-family bromodomains in a patientcomprising administering to the patient in need thereof an effectiveamount of the compound of Formula I.

Another aspect of the present invention is directed to a method ofinhibiting one or more of BET-family bromodomains in a patientcomprising administering to the patient in need thereof an effectiveamount of the pharmaceutical composition comprising the compound ofFormula I and a pharmaceutically acceptable carrier.

Another aspect of the present invention is directed to a method oftreating, preventing, inhibiting, or eliminating a disease or disorderassociated with the activity of one or more BET-family bromodomains in apatient comprising administering to said patient in need thereof atherapeutically effective amount of the compound of Formula I.

One embodiment of the present invention relates a method of treating,preventing, inhibiting, or eliminating a disease or disorder associatedwith the activity of one or more BET-family bromodomains in a patientcomprising administering to said patient in need thereof atherapeutically effective amount of the compound of Formula I, andfurther comprising administering to said patient in need thereof atherapeutically effective amount of another therapeutic agent.

Another embodiment of the present invention relates to a method oftreating, preventing, inhibiting, or eliminating a disease or disorderassociated with the activity of one or more BET-family bromodomains in apatient comprising administering to said patient in need thereof atherapeutically effective amount of the compound of Formula I, whereinsaid disease or disorder is selected from the group consisting ofcancer, inflammatory disorders, irritable bowel syndrome, inflammatorybowel disease, rheumatoid arthritis, obesity, and diabetes.

Another aspect of the present invention is a male contraceptivecomprising a therapeutically effective amount of at least one compoundof Formula I.

Another aspect of the present invention is a male contraceptivecomprising a therapeutically effective amount of at least one compoundof Table 1.

The invention is further illustrated by the compounds shown in Table 1,with IUPAC nomenclature and the structures of the compounds. The tablealso provides reference to the method to make each compound as describedbelow in the examples.

In another embodiment, illustrative compounds of the invention include:

-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-{octahydrocyclopenta[c]pyrrol-5-yl}-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3,3-difluorocyclobutoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-(azetidin-3-ylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-(3-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoroethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoropropoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(4-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(1,3-difluoropropan-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(3,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-2-methylpropanamide;-   (2S)-1-cyclopropanecarbonyl-5-(2-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-1-cyclopropanecarbonyl-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   1-(2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)pyrrolidin-2-one;-   (2S)-1-cyclopropanecarbonyl-5-(4-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(morpholin-4-yl)ethan-1-one;-   methyl    (2S)-5-(2-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   2-(2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-1λ⁶,2-thiazolidine-1,1-dione;-   methyl    (2S)-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   {[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methanesulfonamide;-   methyl    (2S)-5-(4-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylmethanesulfonamide;-   methyl    (2S)-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[2-(oxetan-3-yl)ethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(2,2-difluorocyclopropyl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   3-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyridin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(3-fluorooxetan-3-yl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3,3-difluorocyclobutoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(azetidin-3-ylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-imidazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-({1-[(tert-butoxy)carbonyl]azetidin-3-yl}oxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ⁶-thietan-3-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ⁶-thian-3-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2R)-2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-2-fluoroacetamide;-   (2S)-2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-2-fluoroacetamide;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(3-fluorooxetan-3-yl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-2,2-difluoroacetamide;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-2-methylpropoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   methyl    (2S)-5-[(dimethylcarbamoyl)methoxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N-ethylacetamide;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoroethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N-cyclopropyl-N-methylacetamide;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(azetidin-1-yl)ethan-1-one;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(piperidin-1-yl)ethan-1-one;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoroethoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoroethoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoropropoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(carbamoyldifluoromethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(1,3-difluoropropan-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-2-methylpropoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(1-carbamoyl-1-methylethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(R)-carbamoyl(fluoro)methoxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(S)-carbamoyl(fluoro)methoxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(ethylcarbamoyl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-{[cyclopropyl(methyl)carbamoyl]methoxy}-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[2-(azetidin-1-yl)-2-oxoethoxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[2-oxo-2-(piperidin-1-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[2-(morpholin-4-yl)-2-oxoethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[2-(1,1-dioxo-1λ⁶,2-thiazolidin-2-yl)ethoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(sulfamoylmethoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(dimethylsulfamoyl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[2-(oxetan-3-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(2,2-difluorocyclopropyl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(quinazolin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(1,3-benzoxazol-2-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(1,3-benzoxazol-2-yloxy)-2-methyl-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(pyrimidin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carboxamide;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{1H-pyrazolo[3,4-d]pyrimidin-6-yloxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1,3-thiazol-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carbonitrile;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(3-chloropyridin-2-yl)oxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyridin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(4,6-dimethylpyrimidin-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   6-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridazine-3-carbonitrile;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-propoxy-1,2,3,4-tetrahydroquinoline;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinoline;-   1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-(1-{octahydrocyclopenta[c]pyrrol-5-yl}-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[6-(4-methanesulfonylphenyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-(2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl)ethan-1-one;-   1-[(2S)-5-cyclopropoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(5-methanesulfonylpyridin-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   N-{6-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]pyridin-3-yl}methanesulfonamide;-   2-{[(2S)-1-acetyl-6-(5-methanesulfonylpyridin-2-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-6-(1,3-benzoxazol-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-5-propoxy-6-{pyrazolo[1,5-a]pyridin-2-yl}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-{imidazo[1,2-a]pyridin-2-yl}-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1,3-benzothiazol-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1H-1,3-benzodiazol-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,3,4-tetrahydroquinoline;-   5-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1,3,4-thiadiazol-2-amine;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-(4-chloro-2-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(2-cyano-4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(2-chloro-4-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-cyano-2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate-   2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   methyl    (2S)-5-(2-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2-cyanophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2-cyano-3-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   4-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(3-chloropyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carbonitrile;-   1-[(2S)-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-(4-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(3-cyanopyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(2-cyano-3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(3-chloro-2-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   2-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   2-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-6-fluorobenzonitrile;-   4-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-3-fluorobenzonitrile;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(3-chloro-4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   4-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzamide;-   1-[(2S)-5-(2-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(2-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-carbamoylphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(3-cyano-4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(3-chloro-4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-(2-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-(4-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   4-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-(3-chloro-4-fluorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(3,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(3-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(3,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-(3,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(3-chlorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(3-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline;-   (2S)-5-(3-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(3,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(3,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-(3,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-5-(3,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   5-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1,3,4-thiadiazol-2-amine;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   4-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzamide;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-imidazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-6-[1-(1,1-dioxo-1λ⁶-thian-3-yl)-1H-pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(1,1-dioxo-1λ⁶-thietan-3-yl)-1H-pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(4-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   3-{4-[(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thietane-1,1-dione;-   3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thietane-1,1-dione;-   1-[(2S)-5-(2-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-cyanophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(2-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-carbamoylphenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   4-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   methyl    (2S)-5-(4-chloro-2-cyanophenoxy)-2-methyl-6-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[1-(propan-2-yl)azetidin-3-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-2-methyl-6-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-(1-{2-methyl-octahydrocyclopenta[c]pyrrol-5-yl}-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-{2-methyl-octahydrocyclopenta[c]pyrrol-5-yl}-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(1-ethylazetidin-3-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[1-(propan-2-yl)azetidin-3-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(1-ethylazetidin-3-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(isoquinolin-1-yloxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-(2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-5-(2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(2,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-5-(2,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(2,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-5-(2,3-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(2,3-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-(2,3-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2,3-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(2,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-(2,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-5-(2,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   1-[(2S)-5-(3,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(2,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one-   1-[(2S)-5-{[(E)-2-chloroethenyl]oxy}-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-{1H,2H,3H-pyrazolo[1,5-a]imidazol-7-yl}-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-methanesulfonyl-1H,2H,3H-pyrazolo[1,5-a]imidazol-7-yl}-2-methyl-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-cyclobutoxy-6-[2-(4-hydroxypiperidin-4-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-[2-(4-fluoropiperidin-4-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(3-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(5-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(5-chloropyridin-2-yl)oxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(7H-purin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-cyclobutoxy-6-[1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-6-[1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-[1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-6-[1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione;-   3-{4-[(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(2-oxopiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(2-oxopiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-{1-[(2S)-2-methylazetidin-3-yl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-{1-[(2S)-2-methylazetidin-3-yl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   N-{4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1-cyclopropyl-1H-pyrazol-5-yl}methanesulfonamide;-   N-{4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1-cyclopropyl-1H-pyrazol-5-yl}acetamide;-   methyl    (2S)-5-cyclobutoxy-6-[1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[2-(piperidin-4-yl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-methyl-2-(piperidin-4-yl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   2-{[(2S)-1-acetyl-2-methyl-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N-methylacetamide;-   1-[(2S)-2-methyl-5-(1,2-oxazol-5-ylmethoxy)-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   N-(2-{[(2S)-1-acetyl-2-methyl-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy)}ethyl)methanesulfonamide;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1,2-oxazol-5-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   N-(2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)methanesulfonamide;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N-methylacetamide;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(oxetan-3-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(cyclopentylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[2-(dimethylamino)ethoxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(propan-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(cyclopropylmethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}acetamide;-   1-[(2S)-5-(cyclobutylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(benzyloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(3-methyloxetan-3-yl)methoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(cyclopentyloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}acetonitrile;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-methoxyethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyridin-3-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-5-(cyclohexylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1,3-thiazol-5-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-cyclobutoxy-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-cyclobutoxy-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-cyclobutoxy-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-cyclobutoxy-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-5-(oxan-4-ylmethoxy)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   2-{[(2S)-1-acetyl-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-5-(2-methylpropoxy)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(cyclopentylmethoxy)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(cyclopentylmethoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(pyrrolidin-1-yl)ethan-1-one;-   2-{[(2S)-1-acetyl-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(pyrrolidin-1-yl)ethan-1-one;-   2-{[(2S)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(pyrrolidin-1-yl)ethan-1-one;-   2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(pyrrolidin-1-yl)ethan-1-one;-   (5R)-5-({[(2S)-1-acetyl-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methyl)pyrrolidin-2-one;-   (5R)-5-({[(2S)-1-acetyl-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methyl)pyrrolidin-2-one;-   (5R)-5-({[(2S)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methyl)pyrrolidin-2-one;-   (5R)-5-({[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methyl)pyrrolidin-2-one;-   N-(2-{[(2S)-1-acetyl-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-N-methylmethanesulfonamide;-   N-(2-{[(2S)-1-acetyl-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-N-methylmethanesulfonamide;-   N-(2-{[(2S)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-N-methylmethanesulfonamide;-   N-(2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-N-methylmethanesulfonamide;-   1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-[(3    S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-5-(oxan-4-ylmethoxy)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(dimethylcarbamoyl)methoxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(dimethylcarbamoyl)methoxy]-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(dimethylcarbamoyl)methoxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-5-(2-methylpropoxy)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(cyclopentylmethoxy)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(cyclopentylmethoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-5-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-5-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-(N-methylmethanesulfonamido)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-(N-methylmethanesulfonamido)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-(N-methylmethanesulfonamido)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-5-[2-(N-methylmethanesulfonamido)ethoxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-[(3    S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-[(3    S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-[(3    S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-[(3    S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(5-methyl-1,3-oxazol-2-yl)methoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyridin-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(1,3-benzoxazol-2-ylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(4-methanesulfonylphenyl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-(4-methanesulfonylphenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-6-[4-(ethanesulfonyl)phenyl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-[4-(ethanesulfonyl)phenyl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-6-{4-[2-(dimethylamino)ethoxy]phenyl}-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-{4-[2-(dimethylamino)ethoxy]phenyl}-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-2-methyl-6-[3-(morpholine-4-carbonyl)phenyl]-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-2-methyl-6-[3-(morpholine-4-carbonyl)phenyl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   N-{3-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]phenyl}methanesulfonamide;-   2-{[(2S)-1-acetyl-6-(3-methanesulfonamidophenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-6-(3-methanesulfonylphenyl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-(3-methanesulfonylphenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   N-{4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]phenyl}methanesulfonamide;-   2-{[(2S)-1-acetyl-6-(4-methanesulfonamidophenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-2-methyl-6-[4-(morpholine-4-carbonyl)phenyl]-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-2-methyl-6-[4-(morpholine-4-carbonyl)phenyl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   2-{4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]phenyl}-1λ⁶,2-thiazolidine-1,1-dione;-   2-{[(2S)-1-acetyl-6-[4-(1,1-dioxo-1λ⁶,2-thiazolidin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-6-(1-methanesulfonyl-2,3-dihydro-1H-indol-5-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-(1-methanesulfonyl-2,3-dihydro-1H-indol-5-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   N-{4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]phenyl}-N-methylmethanesulfonamide;-   2-{[(2S)-1-acetyl-2-methyl-6-[4-(N-methylmethanesulfonamido)phenyl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-6-(1-benzofuran-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1H-indol-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   3-{4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione;-   3-{4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thietane-1,1-dione;-   1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyrimidin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-5-{[6-(morpholin-4-yl)pyrimidin-4-yl]oxy}-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(6-cyclopropylpyrimidin-4-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carboxamide;-   1-[(2S)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    6-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carboxylate;-   6-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carboxamide;-   methyl    (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyrimidin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-5-{[6-(morpholin-4-yl)pyrimidin-4-yl]oxy}-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(6-cyclopropylpyrimidin-4-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-{[5-(methoxycarbonyl)pyridin-2-yl]oxy}-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(5-carbamoylpyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline;-   2-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carbonitrile;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline;-   1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(4,6-dimethylpyrimidin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(propan-2-yl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-5-[(5-methoxypyrimidin-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-(1-methanesulfonyl-2,3-dihydro-1H-indol-5-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-(4-methanesulfonylphenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{4-[(2S)-1-acetyl-5-[(5-fluoropyrimidin-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]phenyl}-1λ⁶,2-thiazolidine-1,1-dione;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(3-cyanopyridin-2-yl)oxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(3-cyanopyridin-2-yl)oxy]-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(3-cyanopyridin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(3-cyanopyridin-2-yl)oxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(5-fluoropyrimidin-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(3-carbamoylpyridin-2-yl)oxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-[(3-carbamoylpyridin-2-yl)oxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   4-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylbenzamide;-   methyl    (2S)-5-(3-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-cyclopropanecarbonyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   methyl    6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-2-methyl-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-5-[(3R)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-5-[(3    S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(3R)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(3    S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-[(3    S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;-   1-[(2S)-5-(cyclopentylmethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-({1-[(1E)-prop-1-en-1-yl]-1H-1,3-benzodiazol-2-yl}oxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-({1-[(1Z)-prop-1-en-1-yl]-1H-1,3-benzodiazol-2-yl}oxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-methyl-2-(piperazin-1-yl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[2-(piperazin-1-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-[2-(3-hydroxyazetidin-1-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1,2-oxazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-(1,2-oxazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-8-fluoro-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-1-cyclopropanecarbonyl-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-cyclobutoxy-7,8-difluoro-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(2H-1,2,3-triazol-2-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(2H-1,2,3-triazol-2-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-5-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[5-(piperidin-4-yl)-1H-imidazol-2-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-5-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[5-(piperidin-4-yl)-1H-imidazol-2-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-[(6-methylpyridin-2-yl)oxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-[(2,6-dimethylpyridin-3-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-[(2,6-dimethylpyridin-4-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-[(6-chloropyridin-2-yl)oxy]-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyridin-2-yloxy)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-[(6-fluoropyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-2-methyl-5-[(6-methylpyridin-2-yl)oxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyridin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-2-methyl-5-[(6-methylpyridin-2-yl)oxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-[4-(morpholin-4-yl)-1H-pyrazol-1-yl]-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[4-(piperazin-1-yl)-1H-pyrazol-1-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[4-(piperidin-4-yl)-1H-pyrazol-1-yl]-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-2-methyl-6-[4-(morpholin-4-yl)-1H-pyrazol-1-yl]-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-5-phenoxy-6-[4-(piperazin-1-yl)-1H-pyrazol-1-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-6-carbonitrile;-   (2S)-1-cyclopropanecarbonyl-6-ethynyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(prop-1-yn-1-yl)-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-6-cyano-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-ethynyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-[2-(azetidin-3-yl)-1,3-thiazol-4-yl]-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-[2-(3-fluoroazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-[2-(3-hydroxyazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-[2-(3-methoxyazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-6-(2-carbamoyl-1,3-thiazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[2-(methylcarbamoyl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-(2-acetamido-1,3-thiazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-6-cyclopropyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-6-cyclopropyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-8-fluoro-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-1-cyclopropanecarbonyl-5-(3-methoxyphenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(2,5-difluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(3,4-difluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   2-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   (2S)-1-cyclopropanecarbonyl-5-(3-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(2-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-[(6-methoxypyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-[(6-methoxypyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-5-[(6-methoxypyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ⁶-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   4-{4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione;-   1-[(2S)-6-(1-acetylpiperidin-4-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-6-(1-methanesulfonylpiperidin-4-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   tert-butyl    4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate;-   1-[(2S)-2-methyl-6-(piperidin-4-yl)-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]-N-ethylpiperidine-1-carboxamide;-   methyl    4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]piperidine-1-carboxylate;-   1-[(2S)-6-(1-ethylpiperidin-4-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-5-(phenylamino)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl (2S)-5-cyclobutoxy-6-{1-[(3    S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl (2S)-5-cyclobutoxy-6-{1-[(3    S,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl (2S)-5-(4-fluorophenoxy)-6-{1-[(3    S,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl (2S)-5-(4-fluorophenoxy)-6-{1-[(3    S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-6-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-{1-[(3R,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(4-fluorophenoxy)-6-{1-[(3R,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(2-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(2-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-[(3    S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-cyclobutoxy-6-[5-fluoro-1-(piperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-6-{1-[(3R*,4S*)-4-fluoropyrrolidin-3-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;    and-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-[(3R*,4S*)-4-fluoropiperidin-3-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline.

In another embodiment, suitable compounds of the invention include:

-   methyl    (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-2-methylpropoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   1-[(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(4-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-(2-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-(4-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(2-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(3-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(3-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   1-[(2S)-5-(2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   1-[(2S)-5-[(5-chloropyridin-2-yl)oxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   methyl    (2S)-5-(2-cyano-3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-(3-chloro-4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-5-cyclobutoxy-2-methyl-6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl (2S)-5-cyclobutoxy-6-{1-[(3    S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;-   (2S)-5-(4-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   4-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   2-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;-   methyl    (2S)-6-[1-(1,1-dioxo-11⁶-thietan-3-yl)-1H-pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-5-(3-chloro-4-fluorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-(2-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(3,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-(3,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-5-(2,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-imidazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;-   (2S)-5-(3-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(2,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-(3,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   (2S)-1-cyclopropanecarbonyl-5-(3,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-[(3    S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-5-(2-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   3-{4-[(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-11⁶-thietane-1,1-dione;-   3-{4-[(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-11⁶-thiane-1,1-dione;-   (2S)-1-cyclopropanecarbonyl-5-(4-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   (2S)-1-cyclopropanecarbonyl-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;-   methyl    (2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;-   methyl    (2S)-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;    and-   1-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one.

Method of Synthesizing the Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of the present invention, i.e., compounds of Formulae(I)-(IV), or a pharmaceutically acceptable salt, enantiomer, hydrate,solvate, prodrug, isomer, or tautomer thereof, may be prepared bymethods known in the art of organic synthesis as set forth in part bythe following synthetic schemes. In the schemes described below, it iswell understood that protecting groups for sensitive or reactive groupsare employed where necessary in accordance with general principles orchemistry. Protecting groups are manipulated according to standardmethods of organic synthesis (T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection processes, as well as the reaction conditions andorder of their execution, shall be consistent with the preparation ofcompounds of Formulae (I)-(IV).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of of Formulae (I)-(IV). Accordingly, the present inventionincludes both possible stereoisomers (unless specified in the synthesis)and includes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Illustrative methods includebut are not limited to those methods described below. Compounds of thepresent invention can be synthesized by following the steps outlined inGeneral Schemes 1 and 2, which comprise different sequences ofassembling intermediates. Starting materials are either commerciallyavailable or made by known procedures in the reported literature or asillustrated.

The substituted tetrahydroquinolines (10) described herein can beprepared according to the general procedures outlined in Scheme 1.Oxidative cyclization of 2-chloro-5-methoxyaniline and crotonaldehyde,using chloranil as the oxidant, affords methoxyquinoline 2 as itshydrochloride salt. Catalytic hydrogenation in the presence of basereductively removes the chlorine to provide 3 in good yield. Catalyticasymmetric hydrogenation of 3 with a chiral ruthenium (II) complex athigh pressure provides the desired tetrahydroquinoline 4 in excellentyield. Alternatively, tetrahydroquinoline 4 can be accessed via anasymmetric transfer hydrogenation of 3 using a chiral rhodium (II)complex. Conversion of 4 to phenol 7 can be accomplished via one of tworoutes. Acylation of 4 with an acid chloride or chloroformate anddemethylation with boron tribromide yields affords 7. Phenol 7 can alsobe accessed via demethylation with hydrobromic acid followed byacylation with an acid chloride or chloroformate. Regioselectivebromination of 7 with N-bromosuccinimide provides 8 as the majorproduct. Nucleophilic aromatic substitution or alkylation with theapproporiate aryl or alkyl halide, respectively, yields 9. Aryl bromide9 can be converted to the desired tetrahydroquinline 10 via apalladium-catalyzed Suzuki cross-coupling using the appropriate boronicacid or ester. Alternatively, aryl bromide 9 can be converted to boronicester 11 via a palladium-catalyzed cross-coupling withbis(pinacolato)diboron. Subsequent palladium-catalyzed Suzukicross-coupling with the appropriate aryl halide affords the desiredtetrahydroquinoline 10.

wherein R₅ and R₈ are as defined above.

Alternatively, tetrahydroquinolines (10) can be prepared according tothe procedures outlined in Scheme 2. Iodophenol 13 is available viadiazotization of 2-amino-3-nitrophenol (12) with sodium nitrate in thepresence of sulfuric acid, followed by the addition of potassium iodide.Protection of the phenol with methoxymethylchloride providesintermediate 14 which can undergo a palladium-catalyzed Sonagashiracoupling with (R)-but-3-yn-2-ol to afford 16. Palladium-catalyzedhydrogenation of the triple bond in 16 yields 17 which can be acylatedwith the appropriate acid chloride, anhydride, or chloroformate toprovide 18. Treatment of 18 with methanesulfonyl chloride followed bythe reaction with sodium hydride leads to intramolecular cyclizationaffording tetrahydroquinoline 20. Removal of the methoxymethyl groupyields phenol 7, which can be converted to intermediate 8 viaregioselective bromination with N-bromosuccinimide. Nucleophilicaromatic substitution or alkylation with the approporiate aryl or alkylhalide, respectively, yields 9. Aryl bromide 9 can be converted to thedesired tetrahydroquinline 10 via a palladium-catalyzed Suzukicross-coupling using the appropriate boronic acid or ester.Alternatively, aryl bromide 9 can be converted to boronic ester 11 via apalladium-catalyzed cross-coupling with bis(pinacolato)diboron.Subsequent palladium-catalyzed Suzuki cross-coupling with theappropriate aryl halide affords the desired tetrahydroquinoline 10.

Methods of Using the Disclosed Compounds

One aspect of the present invention relates to a method of modulatingone or more of BET-family bromodomains, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formulae (I), (II), (III), or (IV).

Another aspect of the present invention relates to a method ofinhibiting one or more of BET-family bromodomains, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formulae (I), (II), (III), or (IV).

In another aspect, the present invention relates to a method ofinhibiting one or more of BET-family bromodomains, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the pharmaceutical composition of Formula (I), (II), (III), or(IV).

Another aspect of the present invention relates to a method of treating,preventing, inhibiting, or eliminating a disease or disorder in apatient associated with the inhibition of one or more of BET-familybromodomains, the method comprising administering a therapeuticallyeffective amount of a compound of Formulae (I), (II), (III), or (IV). Inone embodiment, the disease or disorder is selected from the groupconsisting of cancer, inflammatory disorders, irritable bowel syndrome,inflammatory bowel disease, rheumatoid arthritis, obesity and diabetes.

The present invention also relates to the use of an inhibitor of BETfamily bromodomains for the preparation of a medicament used in thetreatment, prevention, inhibition or elimination of a disease ordisorder mediated by BET family bromodomains, wherein the medicamentcomprises a compound of Formulae (I), (II), (III), or (IV).

In another aspect, the present invention the present invention relatesto a method for the manufacture of a medicament for treating,preventing, inhibiting, or eliminating a disease or disorder mediated byBET family bromodomains, wherein the medicament comprises a compound ofFormulae (I), (II), (III), or (IV).

Another aspect of the present invention relates to a pharmaceuticalcomposition for use in a method for treating a disease or disordermediated by BET family bromodomains, wherein the pharmaceuticalcomposition comprises a compound of Formulae (I), (II), (III), or (IV).

In yet another aspect, the present invention relates to a compound foruse in a method for treating a disease or disorder mediated by BETfamily bromodomains, wherein the compound comprises a compound ofFormulae (I), (II), (III), or (IV).

The present invention also relates to the use of an inhibitor of BETfamily bromodomains for the preparation of a medicament used in thetreatment, prevention, inhibition or elimination of tumors, wherein themedicament comprises a compound of Formulae (I), (II), (III), or (IV).

The present invention further relates to the use of an inhibitor of BETfamily bromodomains for the preparation of a medicament used in thetreatment, prevention, inhibition or elimination of cancer, wherein themedicament comprises a compound of Formulae (I), (II), (III), or (IV).

In one embodiment, the present invention relates to the use of aninhibitor of BET family bromodomains for the preparation of a medicamentused in treatment, prevention, inhibition or elimination of diseasesassociated with chronic autoimmune, inflammatory conditions, acuteinflammatory conditions, systemic inflammatory response syndrome, virus,bacterial, or fungal infections, diabetes, and/or obesity. In oneembodiment, the medicament prepared comprises a compound of Formulae(I), (II), (III), or (IV), or a pharmaceutically acceptable salt,enantiomer, hydrate, solvate, prodrug, isomer, or tautomer thereof. Inanother embodiment, the present invention relates to the use of aninhibitor of BET family bromodomains for the preparation of a malecontraceptive, wherein the inhibitor comprises a compound of Formulae(I), (II), (III), or (IV).

Another embodiment of the present invention relates to a compound ofFormulae (I), (II), (III), or (IV), or a pharmaceutically acceptablesalt, enantiomer, hydrate, solvate, prodrug, isomer, or tautomerthereof, or a pharmaceutical composition comprising a compound of thepresent invention, or a pharmaceutically acceptable salt, enantiomer,hydrate, solvate, prodrug, isomer, or tautomer thereof, and apharmaceutically acceptable carrier which provides, upon administrationto a human, a decrease in tumor burden and/or metastases. Thepharmaceutical composition can be administered by oral means or othersuitable means.

In another embodiment, the present invention relates to a compound ofFormula (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier used for the treatment of cancers including but notlimited to cervix, colon, breast, lung, and stomach cancers; hematologiccancer, such as but not limited to leukaemia, lymphoma and multiplemyeloma; midline carcinomas, mesenchymal, hepatic, renal andneurological tumors; and melanoma, squamous cell carcinoma and cutaneousT-cell lymphoma.

In another embodiment, the present invention relates to a compound ofFormulae (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier used for the treatment of a variety of diseases ordisorders related to systemic or tissue inflammation, inflammatoryresponses to infection or hypoxia, cellular activation andproliferation, lipid metabolism, fibrosis and in the prevention andtreatment of viral infections. In one embodiment, the pharmaceuticalcomposition is used.

Another embodiment of the present invention relates to a compound ofFormula (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier used for the treatment of a variety of chronic andinflammatory conditions, including but not limited to rheumatoidarthritis, osteoarthritis, acute gout, psoriasis, systemic lupuserythematosus, multiple sclerosis, Crohn's disease, ulcerative colitis,asthma, chronic obstructive airways disease, pneumonitis, myocarditis,pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullousskin disease, nephrititis, vasculitis, atherosclerosis, Alzheimer'sdisease, depression, Sjogren's syndrome, siloadenitis, central retinalvein occlusion, branched retinal vein occlusion, Irvine-Gass syndrome,parafoveal telangiectasis, retinitis pigmentosa, pars planitis, birdshotretinochoroidopathy, epiretinal membrane, cystic macular edema,maculopathies, vitreomacular traction syndromes, retinal detachment,neuroretinitis, idiopathic macular edema, retinitis, dry eye, vernalkeratoconjuctivitis, atopic keratoconjuctivitis, anterior uveitis, panuveitis, posterior uveitis, uveitis-associated macular edema, scleritis,diabetic retinopathy, diabetic macular edema, age-related maculardystrophy, hepatitis, pancreatitis, primary biliary cirrhosis,sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis,type I diabetes and acute rejection of transplanted organisms.

In another embodiment, the present invention relates to a compound ofFormula (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier used for the treatment of a variety of acuteinflammatory conditions such as acute gout, giant cell arteritis,nephritis including lupus nephritis, vasculitis with organ involvementsuch as glomerulonephritis, vasculitis including giant cell arteritis,Wegner's granulomatosis, Polyarteritis nodosa, Becet's disease, Kawasakidisease, Takayasu's arteritis, pyoderma gangrenosum, vasculitis withorgan involvement and acute rejection of transplanted organs.

Another embodiment of the present invention relates to a compound ofFormula (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier used for the treatment of a variety of diseases ordisorders which involve inflammatory responses to infections withbacteria, viruses, fungi, parasites or their toxins, such as but notlimited to sepsis, sepsis syndrome, septic shock, endotoxaemia, systemicinflammatory response syndrome, multi organ dysfunction syndrome, toxicshock syndrome, acute lung injury, acute respiratory distress syndrome,acute renal failure, fulmiant hepatitis, burns, acute pancreatitis,post-surgical syndromes, sarcoidosis, Herxheimer reactions,encephalitis, myelitis, meningitis, malaria, systemic inflammatoryresponses associated with viral infections, such as but not limited toinfluenza, herpes zoster, herpes simplex and coronavirus.

In another embodiment, the present invention relates to a compound ofFormulae (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier used for the treatment of a variety of conditionsassociated with ischaemia reperfusion injury such as myocardialinfarction, cerebro-vascular ischaemia, acute coronary syndromes, renalreperfusion injury, organ transplantation, coronary artery bypassprocedures, cardio-, pulmonary and bypass procedures, pulmonary, renal,hepatitic, gastrointestinal or peripheral limb embolism.

Another embodiment of the present invention relates to a compound ofFormulae (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier used for treatment of a variety of disorders of lipidmetabolisms such as hypercholesterolemia, atherosclerosis and Alzheimerdisease.

In another embodiment, the present invention relates to a compound ofFormulae (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier used for the treatment of a variety of fibroticconditions such as, but not limited to idiopathic pulmonary fibrosis,renal fibrosis, post-operative structure, keloid scar formation,scleroma and cardial fibrosis.

Another embodiment of the present invention relates to a compound ofFormulae (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention used for the treatment ofa variety of viral infections such as, but not limited to herpes virus,human papilloma virus, adenovirus, poxvirus, and DNA—viruses in general.

In another embodiment, the present invention relates to a compound ofFormulae (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier used for the treatment of a variety of conditionssuch as non-malignant melanoma, actinic keratosis, basal cell melanoma,in situ melanoma, squamous cell carcinoma and cutaneous T-cell lymphoma.

Another embodiment of the present invention relates to a compound ofFormulae (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier used for the treatment of obesity.

In another embodiment, the present invention relates to a compound ofFormulae (I), (II), (III), or (IV) or a pharmaceutical compositioncomprising a pharmaceutically acceptable compound of the presentinvention and a pharmaceutically acceptable carrier used for malecontraceptive.

Another embodiment of the present invention relates to a method oftreating a disease associated with systemic inflammatory responsesyndrome, such as but not limited to sepsis, burns, pancreatitis, majortrauma, hemorrhage and ischaemia, the method comprising administering acompound of Formulae (I), (II), (III), or (IV).

In another embodiment, the present invention relates to a method toreduce incidence of SIRS, onset of shock, multi-organ dysfunctionsyndrome, acute lung injury, acute renal hepatic, cardiac andgastrointestinal injury at the point of diagnosis by administering acompound of Formulae (I), (II), (III), or (IV).

Another embodiment of the present invention relates to a method toreduce incidence of sepsis, hemorrhage, tissue damage, and multipleorgan dysfunction before surgery or any procedure with high risk ofsepsis, the method comprising administering a compound of Formulae (I),(II), (III), or (IV).

The disclosed compounds of the invention can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

The present invention also relates to a pharmaceutical compositioncomprising a compound of Formulae (I), (II), (III), or (IV) and apharmaceutically acceptable carrier. The pharmaceutical acceptablecarrier may further include an excipient, diluent, additive, orsurfactant.

The compounds or pharmaceutical compositions of the invention may beadministered via any mode of administration for therapeutic agents.These modes include systemic or local administration such as oral,nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal ortopical administration modes.

Depending on the intended mode of administration, the disclosedcompounds or compositions can be in solid, semi-solid or liquid dosageform, such as, for example, injectables, tablets, suppositories, pills,time-release capsules, elixirs, tinctures, emulsions, syrups, powders,liquids, suspensions, or the like, sometimes in unit dosages andconsistent with conventional pharmaceutical practices. Likewise, theycan also be administered in intravenous (both bolus and infusion),intraperitoneal, subcutaneous or intramuscular form, and all using formswell known to those skilled in the pharmaceutical arts.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition of the present invention bymixing at least one pharmaceutically acceptable compound of the presentinvention, and, optionally, one or more pharmaceutically acceptablecarriers, additives, or excipients.

In another embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition of the present invention bymixing at least one pharmaceutically acceptable compound of the presentinvention and one or more additional therapeutic agents.

According to one embodiment of the invention, the additional therapeuticagents may be selected from the group consisting of cytotoxic agent,cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan,camptostar, topotecan, paclitaxel, docetaxel, the epothilones,tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide,SCH 66336, tipifarnib (Zarnestra®), R115777, L778,123, BMS 214662,Iressa®, Tarceva®, C225, GLEEVEC®, Intron®, Peg-Intron®, aromatasecombinations, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard,Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman,Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine,Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine,6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, leucovirin,oxaliplatin (ELOXATIN®), Pentostatine, Vinblastine, Vincristine,Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin,Idarubicin, Mithramycin™, Deoxycoformycin, Mitomycin-C, L-Asparaginase,Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Rituximab, C225, Campath, leucovorin, dexamethasone, bicalutamide,carboplatin, letrozole, megestrol, and valrubicin.

The dosage forms of the present invention, may contain a mixture of oneor more compounds of this invention, and may include additionalmaterials known to those skilled in the art as pharmaceuticalexcipients. Stabilizing additives may be incorporated into the deliveryagent solution. With some drugs, the presence of such additives promotesthe stability and dispersibility of the agent in solution. Thestabilizing additives may be employed at a concentration ranging fromabout 0.1 and 5% (W/V), preferably about 0.5% (W/V). Suitable, butnon-limiting, examples of stabilizing additives include gum acacia,gelatin, methyl cellulose, polyethylene glycol, carboxylic acids andsalts thereof, and polylysine. In one embodiment, the stabilizingadditives are gum acacia, gelatin and methyl cellulose.

Examples of pharmaceutical excipients and additives include, but are notlimited to: acidifying agents (acetic acid, glacial acetic acid, citricacid, fumaric acid, hydrochloric acid, diluted hydrochloric acid, malicacid, nitric acid, phosphoric acid, diluted phosphoric acid, sulfuricacid, tartaric acid); Aerosol propellants (butane,dichlorodifluoro-methane, dichlorotetrafluoroethane, isobutane, propane,trichloromonofluoromethane); Air displacements (carbon dioxide,nitrogen); Alcohol denaturants (denatonium benzoate, methyl isobutylketone, sucrose octaacetate); Alkalizing agents (strong ammoniasolution, ammonium carbonate, diethanolamine, diisopropanolamine,potassium hydroxide, sodium bicarbonate, sodium borate, sodiumcarbonate, sodium hydroxide, trolamine); Anticaking agents (seeglidant); Antifoaming agents (dimethicone, simethicone); Antimicrobialpreservatives (benzalkonium chloride, benzalkonium chloride solution,benzelthonium chloride, benzoic acid, benzyl alcohol, butylparaben,cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol,dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium,phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuricnitrate, potassium benzoate, potassium sorbate, propylparaben,propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodiumpropionate, sorbic acid, thimerosal, thymol); Antioxidants (ascorbicacid, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallatesodium formaldehyde sulfoxylate sodium metabisulfite, sodiumthiosulfate, sulfur dioxide, tocopherol, tocopherols excipient);Buffering agents (acetic acid, ammonium carbonate, ammonium phosphate,boric acid, citric acid, lactic acid, phosphoric acid, potassiumcitrate, potassium metaphosphate, potassium phosphate monobasic, sodiumacetate, sodium citrate, sodium lactate solution, dibasic sodiumphosphate, monobasic sodium phosphate); Capsule lubricants (see tabletand capsule lubricant); Chelating agents (edetate disodium,ethylenediaminetetraacetic acid and salts, edetic acid); Coating agents(sodium carboxymethylcellulose, cellulose acetate, cellulose acetatephthalate ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate methacrylic acid copolymer, methylcellulose, polyethyleneglycol, polyvinyl acetate phthalate shellac, sucrose, titanium dioxide,carnauba wax, microcrystalline wax, zein); Colorants (caramel, red,yellow, black or blends, ferric oxide); Complexing agents(ethylenediaminetetraacetic acid and salts (EDTA), edetic acid, gentisicacid ethanolamide, oxyquinoline sulfate); Desiccants (calcium chloride,calcium sulfate, silicon dioxide); Emulsifying and/or solubilizingagents (acacia, cholesterol, diethanolamine (adjunct), glycerylmonostearate, lanolin alcohols, lecithin, mono- and di-glycerides,monoethanolamine (adjunct), oleic acid (adjunct), oleyl alcohol(stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 casteroil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether,polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, propylene glycoldiacetate, propylene glycol monostearate, sodium lauryl sulfate, sodiumstearate, sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan monostearate, stearic acid, trolamine,emulsifying wax); Filtering aids (powdered cellulose, purified siliceousearth); Flavors and perfumes (anethole, benzaldehyde, ethyl vanillin,menthol, methyl salicylate monosodium glutamate, orange flower oil,peppermint, peppermint oil, peppermint spirit, rose oil, stronger rosewater, thymol, tolu balsam tincture, vanilla, vanilla tincture,vanillin); Glidants and/or anticaking agents (calcium silicate,magnesium silicate, colloidal silicon dioxide, talc); Humectants(glycerin, hexylene glycol, propylene glycol, sorbitol); Plasticizers(castor oil, diacetylated monoglycerides, diethyl phthalate glycerin,mono- and di-acetylated monoglycerides, polyethylene glycol, propyleneglycol, triacetin, triethyl citrate); Polymers (e.g., cellulose acetate,alkyl celluloses, hydroxyalkylcelluloses, acrylic polymers andcopolymers); Solvents (acetone, alcohol, diluted alcohol, amylenehydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride,chloroform, corn oil, cottonseed oil, ethyl acetate, glycerin, hexyleneglycol, isopropyl alcohol, methyl alcohol, methylene chloride, methylisobutyl ketone, mineral oil, peanut oil, polyethylene glycol, propylenecarbonate, propylene glycol, sesame oil, water for injection, sterilewater for injection, sterile water for irrigation, purified water);Sorbents (powdered cellulose, charcoal, purified siliceous earth);Carbon dioxide sorbents (barium hydroxide lime, soda lime); Stiffeningagents (hydrogenated castor oil, cetostearyl alcohol, cetyl alcohol,cetyl esters wax, hard fat, paraffin, polyethylene excipient, stearylalcohol, emulsifying wax, white wax, yellow wax); Suspending and/orviscosity-increasing agents (acacia, agar, alginic acid, aluminummonostearate, bentonite, purified bentonite, magma bentonite, carbomer934 p, carboxymethylcellulose calcium, carboxymethylcellulose sodium,carboxymethylcellulose sodium 12, carrageenan, microcrystalline andcarboxymethylcellulose sodium cellulose, dextrin, gelatin, guar gum,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, methylcellulose, pectin,polyethylene oxide, polyvinyl alcohol, povidone, propylene glycolalginate, silicon dioxide, colloidal silicon dioxide, sodium alginate,tragacanth, xanthan gum); Sweetening agents (aspartame, dextrates,dextrose, excipient dextrose, fructose, mannitol, saccharin, calciumsaccharin, sodium saccharin, sorbitol, solution sorbitol, sucrose,compressible sugar, confectioner's sugar, syrup); Tablet binders(acacia, alginic acid, sodium carboxymethylcellulose, microcrystallinecellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum,hydroxypropyl methylcellulose, methylcellulose, polyethylene oxide,povidone, pregelatinized starch, syrup); Tablet and/or capsule diluents(calcium carbonate, dibasic calcium phosphate, tribasic calciumphosphate, calcium sulfate, microcrystalline cellulose, powderedcellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin,lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose,compressible sugar, confectioner's sugar); Tablet disintegrants (alginicacid, microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate starch, pregelatinizedstarch); Tablet and/or capsule lubricants (calcium stearate, glycerylbehenate, magnesium stearate, light mineral oil, polyethylene glycol,sodium stearyl fumarate, stearic acid, purified stearic acid, talc,hydrogenated vegetable oil, zinc stearate); Tonicity agent (dextrose,glycerin, mannitol, potassium chloride, sodium chloride); Vehicle:flavored and/or sweetened (aromatic elixir, compound benzaldehydeelixir, iso-alcoholic elixir, peppermint water, sorbitol solution,syrup, tolu balsam syrup); Vehicle: oleaginous (almond oil, corn oil,cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate,mineral oil, light mineral oil, myristyl alcohol, octyldodecanol, oliveoil, peanut oil, persic oil, sesame oil, soybean oil, squalane);Vehicle: solid carrier (sugar spheres); Vehicle: sterile (bacteriostaticwater for injection, bacteriostatic sodium chloride injection);Viscosity-increasing (see suspending agent); Water repelling agent(cyclomethicone, dimethicone, simethicone); and Wetting and/orsolubilizing agent (benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docusate sodium, nonoxynol 9, nonoxynol 10,octoxynol 9, poloxamer, polyoxyl 35 castor oil, polyoxyl 40,hydrogenated castor oil, polyoxyl 50 stearate, polyoxyl 10 oleyl ether,polyoxyl 20, cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate,sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, tyloxapol) may be used as excipients. This listis not meant to be exclusive, but instead merely representative of theclasses of excipients and the particular excipients which may be used indosage forms of the present invention.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

For preparing pharmaceutical compositions from the compounds describedin this disclosure inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.For example, water or water-propylene glycol solutions for parenteralinjection or addition of sweeteners and opacifiers for oral solutions,suspensions and emulsions. Liquid form preparations may also includesolutions for intranasal administration.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g., nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein, oras known to those skilled in the art.

Since the compounds of this invention are intended for use inpharmaceutical compositions a skilled artisan will understand that theycan be provided in substantially pure forms for example, at least 60%pure, more suitably at least 75% pure, preferably at least 85% pure andmost preferably at least 98% pure (w/w).

The pharmaceutical preparation may be in a unit dosage form. In suchform, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 1000 mg, from about 1 mg toabout 500 mg, from about 1 mg to about 250 mg, or from about 1 mg toabout 25 mg, according to the particular application.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. Effective dosage amountsof the disclosed compounds, when used for the indicated effects, rangefrom about 0.5 mg to about 5000 mg of the disclosed compound as neededto treat the condition. Compositions for in vivo or in vitro use cancontain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250,2500, 3500, or 5000 mg of the disclosed compound, or, in a range of fromone amount to another amount in the list of doses. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day or 1 mg/day to 200 mg/day, in two to fourdivided doses.

The compounds of Formulae I through IV can form salts which are alsowithin the scope of this invention. Reference to a compound of theFormula herein is understood to include reference to salts thereof,unless otherwise indicated.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates), and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

The synthetic schemes are presented for the synthesis of certaincompounds herein disclosed. The process and results for the assaystesting BET family bromodomain inhibition and effects on a cancer cellline proliferation are also described.

DEFINITIONS USED IN THE FOLLOWING SCHEMES AND ELSEWHERE HEREIN ARE

-   Ac₂O acetic anhydride-   Boc tert-butoxycarbonyl-   DCE 1,2-dichloroethane-   DCM dichloromethane or methylene chloride-   DIPEA N,N-diisopropylethylamine-   DMAP 4-(dimethylamino)pyridine-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DPPA diphenylphosphoryl azide-   dppf bis(diphenylphosphino)ferrocene-   Et₃N triethylamine-   EtOAc ethyl acetate-   EtOH ethanol-   h hours-   HATU    2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate-   HCl hydrogen chloride-   HPLC high performance liquid chromatography-   (i-Pr)₂NEt N,N-diisopropylethylamine-   LC/MS liquid chromatography/mass spectrometry-   K₂CO₃ potassium carbonate-   MS mass spectrometry-   NBS N-bromosuccinimide-   Ph₃P triphenylphosphine-   PhCHO benzaldehyde-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium-   p-TsOH para-toluenesulfonic acid-   rt room temperature-   TFAA trifluoroacetic anhydride-   THF tetrahydrofuran-   XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Materials

Unless otherwise noted, all materials were obtained from commercialsuppliers and were used without further purification. Anhydrous solventswere obtained from Sigma-Aldrich (Milwaukee, Wis.) and used directly.All reactions involving air- or moisture-sensitive reagents wereperformed under a nitrogen atmosphere.

Unless otherwise noted, mass-triggered HPLC purification and/or purityand low resolution mass spectral data were measured using either: (1)Waters Acquity ultra performance liquid chromatography (UPLC) system(Waters Acquity UPLC with Sample Organizer and Waters Micromass ZQ MassSpectrometer) with UV detection at 220 nm and a low resonanceelectrospray positive ion mode (ESI) (Column: Acquity UPLC BEH C₁₈ 1.7μm 2.1×50 mm; gradient: 5-100% Solvent B (95/5/0.09%:Acetonitrile/Water/Formic Acid) in Solvent A (95/5/0.1%: 10 mM AmmoniumFormate/Acetonitrile/Formic Acid) for 2.2 min then 100-5% Solvent B inSolvent A for 0.01 min then hold at 5% Solvent B in Solvent A for 0.29min) or (2) Waters HT2790 Alliance high performance liquidchromatography (HPLC) system (Waters 996 PDA and Waters ZQ Single QuadMass Spectrometer) with UV detection at 220 nm and 254 nm and a lowresonance electrospray ionization (positive/negative) mode (ESI)(Column: XBridge Phenyl or C18, 5 μm 4.6×50 mm; gradient: 5-95% SolventB (95% methanol/5% water with 0.1% Formic Acid) in Solvent A (95%water/5% methanol with 0.1% Formic Acid) for 2.5 min then hold at 95%Solvent B in Solvent A for 1 min (purity and low resolution MS only).

Example 1 Intermediate1—(2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline

Step 1. 8-chloro-5-methoxy-2-methylquinoline hydrochloride

A 1000-mL 3-necked round-bottom flask was charged with2-chloro-5-methoxyaniline (50 g, 317 mmol), n-butanol (120 mL),concentrated hydrochloric acid (37%, 90 mL), and chloranil(tetrachloro-1,4-benzoquinone) (78 g, 317 mmol). The resulting solutionstirred for 1 h at 100° C. in an oil bath. A solution of(E)-crotonaldehyde (28.9 mL, 349 mmol) in n-butanol (50 mL) was addeddropwise over 1 h. The resulting solution stirred for 1 h at 100° C. inan oil bath and was then cooled to 70° C. Tetrahydrofuran (650 mL) wasadded, and the reaction mixture stirred for 1 h at 70° C. and was thencooled to 0° C. The resulting precipitate was held at 0-5 OC for 1 h.The mixture was filtered, the solids were washed with cold (ca. 0° C.)THF (2×350 mL), and then dried in an oven to afford8-chloro-5-methoxy-2-methylquinoline hydrochloride (83.0 g, 74%) as ayellow solid. MS (ES, m/z): 208 [M+H]⁺

Step 2. 5-methoxy-2-methylquinoline

A 1000-mL round-bottom flask was charged with8-chloro-5-methoxy-2-methylquinoline hydrochloride (50.0 g, 204.8 mmol),methanol (300 mL), aqueous sodium hydroxide solution (3 M, 205 mL), and10% palladium on active carbon (25 g). The system was purged withhydrogen gas, and the resulting mixture was stirred under a hydrogenatmosphere for 3 h at room temperature. The reaction mixture wasfiltered through a pad of Celite and concentrated under vacuum to removemost of methanol. The resulting solution was extracted with ethylacetate (2×2000 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (gradientelution with 0-20% ethyl acetate/petroleum ether) to afford5-methoxy-2-methylquinoline (36 g, 63%) as a yellow solid. MS (ES, m/z):174 [M+H]⁺

Step 3. (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline(Intermediate 1)

A 30-mL glass-lined stainless steel reactor with a magnetic stirring barwas charged with 5-methoxy-2-methylquinoline (4.0 g, 23.1 mmol),Ru(OTf)(η6-hexamethylbenzene)((S,S)-TsDPEN)([N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN][(1,2,3,4,5,6-η)-1,2,3,4,5,6-hexamethylbenzene](1,1,1-trifluoromethanesulfonato-κO)-ruthenium,prepared according to the procedure in J. Am. Chem. Soc. 2011, 133,9878-9891) (0.100 g, 0.13 mmol) and methanol (10 mL). The reactor wasclosed and hydrogen gas was initially introduced in at a pressure of 50atm, before being reduced to 1 atm. After this procedure was repeatedthree times, the reactor was pressurized with hydrogen to 50 atm. Theresulting mixture was stirred under this hydrogen pressure for 24 h atroom temperature. After carefully releasing the hydrogen, the reactionmixture was concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (gradient elution with 0-20% ethylacetate/petroleum ether) to afford(2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (4.0 g, 98%, >99%ee) as yellow oil. MS (ES, m/z): 178 [M+H]⁺

Example 2 Intermediate 1—HCl salt.(2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline hydrochloride

Step 1. (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline

A three-necked, 2-L round bottomed flask equipped with an overheadstirrer, thermocouple, and nitrogen inlet was charged with methanol(1350 mL) and formic acid (51.8 mL, 1350 mmol).

The flask was lowered into an ice-water bath and when the internaltemperature reached 13° C., triethylamine (75 mL, 540 mmol) was slowlyadded, causing the internal temperature to rise to 21° C. Next,5-methoxy-2-methylquinoline (58.47 g, 338 mmol) was added in oneportion, and the resulting solution was cooled to 0° C. Finally,Cp*RhCl[(S,S)-TsDPEN]([N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5-q)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]rhodium,prepared according to the procedure in Org. Lett. 1999, 1, 841) (2.157g, 3.38 mmol) was added in one portion. The ice bath was left in placeand allowed to slowly expire. After 22 h (internal temperature=17° C.),additional formic acid (12.95 mL, 338 mmol) was added to the reactionmixture. The dark solution stirred at room temperature for 4 days. Aftera total of 5 days, the solution was concentrated under reduced pressure.The concentrated reaction mixture was re-dissolved in ethyl acetate (ca.750 mL) and washed twice with saturated aqueous sodium bicarbonatesolution (250 mL, then 100 mL), and finally with 5% aqueous sodiumchloride solution (100 mL). The ethyl acetate extract was thenconcentrated under reduced pressure to afford 64.7 g of a dark syrup.Chiral HPLC analysis showed the material to have an enantiopurity of97.2:2.8 e.r. (94.4% ee). (Chiral HPLC method: Column: ODH; Method: ODH98% Hexane 2% IPA; UV: 254, Flow: 0.5 mL/min). The crude(S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (59.8 g, 338 mmol,100% yield) was used without further purification in the salt formation(assumed 100% yield). MS (ES, m/z): 178 [M+H]⁺

Step 2. (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinolinehydrochloride (Intermediate 1-HCl salt)

A three-necked, 500-mL round-bottomed flask equipped with a magneticstir bar and thermocouple was charged with ethanol (160 mL), and thesolution was cooled to 0° C. Acetyl chloride (26.4 mL, 372 mmol) wasslowly added over 45 min, maintaining the internal temperature below 8°C. The ice bath was removed and the HCl solution (˜2 M) was allowed towarm for about 30 min (internal temperature=15° C.).

A three-necked, 1-L round-bottomed flask equipped with an overheadstirrer, thermocouple, and nitrogen inlet was charged with a solution ofcrude (S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (59.9 g, 338mmol) in ethyl acetate (600 mL). To this solution was then added thefreshly prepared HCl solution (ca. 2 M in ethanol, 86 mL, 372 mmol) at17° C. As the HCl solution was being added, the mixture initially becamecloudy but then became a clear solution upon complete addition. Theinternal temperature rose to 26° C. The clear solution was stirred atambient temperature, and after 10-15 min, a granular precipitate formed.The slurry was stirred at ambient temperature for 4.5 h, then filteredon a glass, 600-mL Buchner funnel. The flask and solids were rinsed withfresh ethyl acetate, filtered, and dried on the filter under suction anda positive pressure of nitrogen to afford(S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline hydrochloride (64.43g, 89%) as a cream-colored, free-flowing, granular solid. Chiral HPLCanalysis showed the salt to have an enantiopurity of 98.9:1.1 e.r.(97.8% ee). (Chiral HPLC method: Column: ODH; Method: ODH 98% Hexane 2%IPA; UV: 254, Flow: 0.5 mL/min). MS (ES, m/z): 178 [M+H]⁺

Example 3 Intermediate2—(2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol

Step 1a.(2S)-1-cyclopropanecarbonyl-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline

A 1000-mL 3-necked round-bottom flask was charged with(2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (47.41 g, 267.5mmol), dichloromethane (500 mL), and pyridine (38 mL).Cyclopropanecarbonyl chloride (28.4 g, 271.7 mmol) was added dropwisewith stirring at 0° C., and the resulting solution stirred for 3 h at 0°C. The reaction mixture was poured into 400 mL of water/ice, and thenwashed with 2 N hydrochloric acid (1×100 mL) and brine (3×300 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was purified via column chromatography on silica gel(eluting with 0-15% ethyl acetate/petroleum ether) to afford(2S)-1-cyclopropanecarbonyl-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline(64.6 g, 98%) as a yellow solid. MS (ES, m/z): 246 [M+H]⁺

Step 2a.(2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol

A 1000-mL round-bottom flask was charged with(2S)-1-cyclopropanecarbonyl-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline(15.0 g, 61.2 mmol) and dichloromethane (300 mL). A solution of borontribomide (1 M in dichloromethane, 308 mL, 308 mmol) was added dropwiseat 0° C., and the resulting solution stirred for 1 h at 0° C. Thereaction mixture was then poured into 500 mL of water/ice and extractedwith dichloromethane (2×500 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was purified via column chromatography on silica gel(eluting with 0-80% ethyl acetate/petroleum ether) to afford(2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol(9.4 g, 66%) as an off-white solid. MS (ES, m/z): 232 [M+H]⁺

Step 1b. (S)-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol hydrobromide

A 500-mL round bottomed flask equipped with a heating mantle and anoverhead stirrer was charged with(S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline hydrochloride (20 g,94 mmol) followed by hydrobromic acid (48%, 154 mL, 1361 mmol). Themixture was heated to 100° C., and the reaction readily proceeded withloss of bromomethane through an uncooled reflux condenser. After 1 h,solids precipitated from the solution. The reaction was complete after10 h at 100° C. and allowed to cool to ambient temperature whilestirring overnight. The reaction mixture was placed in an ice bath andstirred for 2 h at 0-5° C. The resulting white slurry was filtered andthe pot and solids were washed with 20 mL of ice cold water. The filtercake was dried on a Buchner funnel under nitrogen blanket to afford(S)-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol hydrobromide (21.71 g, 95%)as a white powder. MS (ES, m/z): 164 [M+H]⁺

Step 2b.(2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol

A 1000-mL round bottomed flask fitted with a nitrogen inlet, overheadstirrer, addition funnel, and thermocouple, was charged with(S)-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol hydrobromide (20 g, 82mmol), followed by anhydrous DMF (109 mL), and pyridine (19.8 mL, 246mmol). Cyclopropanecarbonyl chloride (7.43 mL, 82 mmol) was addeddropwise over 30 minutes while holding temperature below 20° C. with acool water bath. Following completion of the addition, the reactionmixture was stirred for 1.5 h at ambient temperature. The pot was cooledto 0° C. in an ice bath and 0.29 M aqueous HCl solution (315 mL) wasadded dropwise over 15 minutes. The slurry was stirred for 90 minutes inthe ice bath before being filtered. The pot and filter cake were washedwith 25 mL of ice water. The filter cake was dried under nitrogen on aBuchner funnel to afford(2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol

(17.16 g, 91%) as an off-white powder. MS (ES, m/z): 232 [M+H]⁺

Step 3.(2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol(Intermediate 2)

Into a 1000-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed(2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol(4.0 g, 17.3 mmol) in acetonitrile (600 mL) and dichloromethane (150mL). The solution was cooled to −10° C., and a solution ofN-bromosuccinimide (3.08 g, 17.3 mmol) in acetonitrile (50 mL) was addeddropwise over 3 h. The resulting solution stirred for 30 minutes at −10°C., and was then concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (eluting with 0-20% ethylacetate/petroleum ether) to afford(2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol(3.6 g, 68%) as a light yellow solid. MS: (ES, m/z): 310, 312 [M+H]⁺

Example 4 Intermediate 3.(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Step 1. 2-iodo-3-nitrophenol

A 1-L, three-necked, round bottomed flask equipped with an overheadstirrer, thermocouple, and nitrogen inlet was charged with2-amino-3-nitrophenol (17.5 g, 114 mmol), DMSO (280 mL), and 30%sulfuric acid (280 mL, 1575 mmol). The dark red-orange solution washeated to 50° C. After 45 min, heating was discontinued, and thesolution was cooled to 3° C. (once the solution reached 13° C., aprecipitate formed). Next, a solution of sodium nitrite (10.97 g, 159mmol) in water (35 mL) was slowly added to the slurry while maintainingthe internal temperature below 5° C.; the addition took ca. 5-7 min. Thesolution was stirred at 0° C. After 1 h, a solution of potassium iodide(52.8 g, 318 mmol) in water (105 mL) was slowly added over a 5 minperiod. After 1 h, the ice bath was removed, and the reaction mixturewas allowed to warm to room temperature and stirred for 20 h. Thereaction mixture was then extracted with methyl tert-butyl ether (1×800mL and 1×400 mL). The combined methyl tert-butyl ether extracts werewashed with 20% aqueous sodium thiosulfate solution (2×200 mL) followedby 5% aqueous sodium chloride solution (2×200 mL). The organic extractwas concentrated under reduced pressure. Toluene (200 mL) was added andthen removed under reduced pressure to afford 2-iodo-3-nitrophenol (30.2g, 100%) as a brown powder. ¹H NMR (400 MHz, CDCl₃): δ 7.44 (dd, J=8.0,1.5 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.24 (dd, J=8.0, 1.5 Hz, 1H), 5.97(br, 1H) ppm.

Step 2. 2-iodo-1-(methoxymethoxy)-3-nitrobenzene

A 200-mL round bottomed flask equipped with a magnetic stir bar wascharged with ethyl acetate (37 mL), dimethoxymethane (12.25 mL, 137mmol), and zinc acetate (2.51 mg, 0.014 mmol). Next, acetyl chloride(9.73 mL, 137 mmol) was slowly added over a 20 min period. The solutionwas stirred at room temperature for 2 h. This chloromethyl methyl ethersolution was then added to a solution of 2-iodo-3-nitrophenol (30.2 g,114 mmol) in N,N-dimethylformamide (170 mL). The resulting solution wascooled to 0° C. and slowly treated with diisopropylethylamine (49.8 mL,285 mmol) over a 20 min period. The ice bath was left in place, and thereaction mixture stirred overnight as the ice bath slowly expired. Thereaction mixture was then diluted with ethyl acetate and partitionedbetween water (340 mL) and ethyl acetate (500 mL). The organic layer wasseparated and washed with half-saturated aqueous sodium bicarbonatesolution (1×340 mL) and 5% aqueous sodium chloride solution (1×340 mL,then 1×200 mL). The organic layer was then concentrated under reducedpressure to afford a dark brown syrup (33.6 g), which crystallized uponstanding. The crude product was dissolved in a small amount ofdichloromethane and purified by filtration through a pad of silica gel(14 cm(d)×6 cm(h), eluting with 3:2 hexanes-dichloromethane) to afford2-iodo-1-(methoxymethoxy)-3-nitrobenzene (30.2 g, 86%) as a pale yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ 7.39 (t, J=8.1 Hz, 1H), 7.34 (dd,J=8.0, 1.6 Hz, 1H), 7.25 (dd, J=8.1, 1.6 Hz, 1H), 5.30 (s, 2H), 3.52 (s,3H) ppm.

Step 3. (R)-4-(2-(methoxymethoxy)-6-nitrophenyl)but-3-yn-2-ol

A two-necked, 100-mL round bottomed flask equipped with a magnetic stirbar was charged with 2-iodo-1-(methoxymethoxy)-3-nitrobenzene (5.0 g,16.18 mmol), copper(I) iodide (0.154 g, 0.809 mmol),bis(triphenylphosphine)palladium(II) chloride (0.284 g, 0.404 mmol),N,N-dimethylacetamide (25 mL), and triethylamine (9.02 mL, 64.7 mmol).Nitrogen was bubbled through the dark orange solution for severalminutes and then (R)-but-3-yn-2-ol (1.33 mL, 17.0 mmol) was added, whichcaused the solution to lighten in color considerably. The solution wasthen heated to 70° C. for 10 h, at which point heating was discontinuedand the reaction mixture allowed to cool to rt. After stirring at rt for10 h, the reaction mixture was diluted with isopropyl acetate and washedwith water (50 mL), saturated aqueous ammonium chloride solution (50mL), and 5% aqueous sodium chloride solution (2×50 mL). The organiclayer was concentrated under reduced pressure to afford a dark brownsyrup (4.7 g). The crude product was purified by flash chromatography onsilica gel (eluting with 2:1 hexanes-ethyl acetate, then 3:2hexanes-ethyl acetate, and finally 1:1 hexanes-ethyl acetate) to afford(R)-4-(2-(methoxymethoxy)-6-nitrophenyl)but-3-yn-2-ol (2.1 g, 52%). MS(ESI, pos. ion) m/z 274 [M+23]⁺.

Step 4. (R)-4-(2-amino-6-(methoxymethoxy)phenyl)butan-2-ol

A 400-mL Parr bottle charged with(R)-4-(2-(methoxymethoxy)-6-nitrophenyl)but-3-yn-2-ol (2.9 g, 11.54mmol), methanol (58 mL), and 10% palladium on carbon (50% water, 1.228g, 0.577 mmol) was pressurized to 39 psig with hydrogen and then shaken.Hydrogen was quickly consumed, and within 15 min, the pressure haddropped to 0 psig. The bottle was re-pressurized to 39 psig and shakingwas continued. The pressure dropped to ca. 20 psig over the next 15 minand stabilized. The bottle was re-pressurized to 34 psig and held therewith continued shaking for 2 h. The mixture was flushed with nitrogen,and then filtered through a pad of Celite. The bottle and catalyst wererinsed with methanol, and the filtrate concentrated under reducedpressure. Toluene was added and the mixture was concentrated to afford(R)-4-(2-amino-6-(methoxymethoxy)phenyl)butan-2-ol (2.60 g, 100%) as adark yellow syrup which was used without further purification. MS (ESI,pos. ion) m/z 248 [M+23]⁺.

Step 5. (R)—N-(2-(3-hydroxybutyl)-3-(methoxymethoxy)phenyl)acetamide

A solution of crude (R)-4-(2-amino-6-(methoxymethoxy)phenyl)butan-2-ol(2.60 g, 11.54 mmol) and pyridine (2.80 mL, 34.6 mmol) indichloromethane (52 mL) was cooled to 0° C. and treated with aceticanhydride (1.14 mL, 12.1 mmol). The ice bath was removed and thereaction mixture stirred at room temperature. After 45 min, the solutionwas washed with 5% aqueous sodium chloride solution (2×20 mL) and thenconcentrated under reduced pressure. Toluene (ca. 100 mL) was added andthe mixture was concentrated. The residue was purified by columnchromatography on silica gel (gradient elution with 25-100% ethylacetate-hexanes) to afford(R)—N-(2-(3-hydroxybutyl)-3-(methoxymethoxy)phenyl)acetamide (2.7 g,88%) as a pale yellow syrup. MS (ESI, pos. ion) m/z 290 [M+23]⁺.

Step 6. (R)-4-(2-acetamido-6-(methoxymethoxy)phenyl)butan-2-ylmethanesulfonate

A solution of(R)—N-(2-(3-hydroxybutyl)-3-(methoxymethoxy)phenyl)acetamide (4.0 g,14.96 mmol) in acetonitrile (40 mL) was treated with triethylamine (3.13mL, 22.44 mmol) and cooled to 0° C. Methanesulfonyl chloride (1.46 mL,18.7 mmol) was slowly added and a precipitate formed immediately. Theslurry was stirred at 0° C. After 3 h, the reaction mixture was dilutedwith ethyl acetate and poured into 5% aqueous sodium chloride solution(50 mL). The layers were separated, and the organic layer washed withadditional 5% aqueous sodium chloride solution (40 mL). The combinedaqueous layers were extracted with ethyl acetate, and the combinedorganic layers were concentrated under reduced pressure. The residue wasdissolved in toluene (50-75 mL), which was then removed under reducedpressure to afford(R)-4-(2-acetamido-6-(methoxymethoxy)phenyl)butan-2-yl methanesulfonate(5.17 g, 100%) as an amber syrup. The crude was used without furtherpurification. MS (ESI, pos. ion) m/z 250 [M−95]⁺.

Step 7.(S)-1-(5-(methoxymethoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

(R)-4-(2-Acetamido-6-(methoxymethoxy)phenyl)butan-2-yl methanesulfonate(3.39 g, 9.8 mmol) was dissolved in N,N-dimethylformamide (34 mL). Thesolution was cooled to 0° C., and sodium hydride (60% in mineral oil,0.510 g, 12.74 mmol) was added in one portion. The ice bath was removedand the reaction mixture stirred at room temperature. After 2 h, thereaction mixture was cooled to 0° C. with an ice bath and slowly dilutedwith water (40 mL). The mixture was extracted with ethyl acetate. Theorganic layer was separated and washed with 5% aqueous sodium chloridesolution (2×40 mL). The combined aqueous layers were extracted withethyl acetate, and the combined organic extracts were concentrated underreduced pressure to afford a dark amber syrup (3.9 g). The crude productwas purified via column chromatography on silica gel (eluting with 2:1hexanes-ethyl acetate, followed by 3:2 hexanes-ethyl acetate) to afford(S)-1-(5-(methoxymethoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(1.74 g, 71%) as a dark yellow-orange syrup. MS (ESI, pos. ion) m/z 250[M+1]⁺.

Step 8. (S)-1-(5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of(S)-1-(5-(methoxymethoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(1.6 g, 6.42 mmol) in methanol (16 mL) was treated with concentratedhydrochloric acid (1.0 mL, 12.8 mmol) at rt. The solution was heated to50° C. for 90 min. Heating was discontinued, and the solution wasallowed to slowly cool to room temperature overnight. Methanol wasremoved under reduced pressure and the residue was partitioned betweendichloromethane and water. The aqueous layer was separated and extractedwith dichloromethane. The combined organic extracts were concentratedunder reduced pressure. The residue was dissolved in acetonitrile (ca.20-30 mL), and then concentrated under reduced pressure to afford(S)-1-(5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.23 g,93%) as an off-white to tan solid. MS (ESI, pos. ion) m/z 206 [M+1]⁺.

Step 9.(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(Intermediate 3)

A solution of(S)-1-(5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.2 g,5.85 mmol) in acetonitrile (24 mL) was cooled to 0° C. and treated withN-bromosuccinimide (1.041 g, 5.85 mmol) in one portion. The solutionturned dark yellow-orange in color initially, then faded to a paleorange color over the next 10-15 min. After 30 min, the solution wasconcentrated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (eluting with 8:1dichloromethane-ethyl acetate followed by 7:1 dichloromethane-ethylacetate) to afford(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(1.37 g, 82%). MS (ESI, pos. ion) m/z 284, 286 [M+1]⁺.

Intermediate 3 could also be synthesized from(2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline following theprocedure used for the synthesis of(2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol,substituting acetyl chloride for cyclopropanecarbonyl chloride. MS: (ES,m/z): 284, 286 [M+H]⁺

Example 5 Intermediate 4. Methyl(S)-6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Methyl(S)-6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized following the procedure for(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanonesubstituting methyl chloroformate for acetyl chloride in Step 5 or from(2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline following theprocedure used for the synthesis of(2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol,substituting methyl chloroformate for cyclopropanecarbonyl chloride. MS:(ES, m/z): 300, 302 [M+H]⁺

Example 6 Intermediates 5 and 6.rac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (5) andrac-6-bromo-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (6)

Step 1. 3-amino-4-chlorophenol

A 100-mL round bottomed flask equipped with a magnetic stir bar wascharged with 4-chloro-3-nitrophenol (6.0 g, 34.6 mmol) and acetic acid(60 mL). Iron powder (325 mesh) (19.31 g, 346 mmol) was added, and themixture was heated at 100° C. for 30 min. The mixture was cooled to roomtemperature and diluted with water (40 mL). The mixture was thenfiltered through a pad of Celite and rinsed with water. The filtrate wasthen extracted with ethyl acetate, and the combined extracts wereconcentrated under reduced pressure. Heptane (ca. 100 mL) was added tothe filtrate and then removed under reduced pressure in order to removeresidual acetic acid and water. This was repeated. The residue wasdissolved in acetonitrile and concentrated under reduced pressure. Theresulting solid was suspended in heptane and concentrated under reducedpressure to afford 3-amino-4-chlorophenol (4.38 g, 88%) as a palepurple/amber solid. MS (ESI, pos. ion) m/z 144 [M+1].

Step 2. 2-chloro-5-phenoxyaniline

A heat gun-dried 100-mL round bottomed flask equipped with a magneticstir bar was charged with potassium phosphate (5.91 g, 27.9 mmol),picolinic acid (0.171 g, 1.393 mmol), copper(I) iodide (0.133 g, 0.697mmol), 3-amino-4-chlorophenol (2.0 g, 13.93 mmol), dimethylsulfoxide(27.9 mL), and iodobenzene (3.41 g, 16.72 mmol). The resulting mixturewas heated to 80° C. After 15 h, the reaction mixture was subjected toan aqueous workup to afford the crude product, which was then purifiedby flash chromatography to afford pure 2-chloro-5-phenoxyaniline (2.61g, 85%). MS (ESI, pos. ion) m/z 220 [M+1].

Step 3. 8-chloro-2-methyl-5-phenoxyquinoline

A 50-mL round bottomed flask equipped with a magnetic stir bar wascharged with 2-chloro-5-phenoxyaniline (1.25 g, 5.69 mmol), chloranil(1.399 g, 5.69 mmol), n-butanol (5 mL), and concentrated hydrochloricacid (1.61 mL, 19.3 mmol). The mixture was heated to 100° C. and then asolution of (E)-but-2-enal (0.566 mL, 6.83 mmol) in n-butanol (2 mL) wasslowly added over 5 min. The mixture turned a dark amber/brown solution.After 45 min, heating was discontinued. After cooling, the solution wasdiluted with THF (30 mL). The solution was then concentrated underreduced pressure to remove the THF. Ethyl acetate was added and aprecipitate formed. The slurry was stirred for 15 min and then filtered.The solids were rinsed with ethyl acetate and dried to yield 1.9 g of adark yellow-brown solid. This material was suspended in 25 mL of 1 Naqueous sodium hydroxide solution, and the slurry was stirred rapidlyfor 30 min and then filtered. The solids were thoroughly rinsed withwater and dried to afford 8-chloro-2-methyl-5-phenoxyquinoline (0.95 g,62%) as an off-white solid. MS (ESI, pos. ion) m/z 270 [M+1].

Step 4. 2-methyl-5-phenoxyquinoline

A Parr bottle was charged with 8-chloro-2-methyl-5-phenoxyquinoline(0.93 g, 3.45 mmol), methanol (20 mL), and 3 M aqueous sodium hydroxidesolution (3.79 mL, 11.38 mmol). The bottle was flushed with nitrogen,and 10% palladium on carbon (0.5 g, 0.470 mmol) was added. The mixturewas then shaken under an atmosphere of hydrogen (30 psig). After 4.5 h,the mixture was filtered through a pad of Celite. The bottle and filterpad were rinsed with methanol. The filtrate was concentrated underreduced pressure. The residue was then partitioned between ethyl acetateand 5% aqueous sodium chloride solution (25 mL). The layers wereseparated, and the organic layer washed again with 5% aqueous sodiumchloride solution (25 mL). The aqueous washes were extracted once withethyl acetate, and the combined extracts were concentrated to affordcrude 2-methyl-5-phenoxyquinoline (0.82 g, 101%) as a pale yellow-orangesyrup which was used without further purification. MS (ESI, pos. ion)m/z 236 [M+1].

Step 5. rac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (Intermediate5)

A glass, screw-cap vial equipped with a magnetic stir bar was chargedwith 2-methyl-5-phenoxyquinoline (0.05 g, 0.213 mmol), methanol (1 mL),and nickel(II) chloride (4.96 mg, 0.038 mmol). Sodium borohydride (0.032g, 0.850 mmol) was added portion-wise over 30 sec at rt. The reactionmixture turned dark purple (almost black), and an exotherm was observed.After 10 min, the reaction mixture was concentrated under a stream ofnitrogen. The residue was then treated with 1 N aqueous sodium hydroxidesolution (1 mL) and dichloromethane (2-3 mL). The resulting emulsion wasfiltered through a pad of Celite and washed with ethyl acetate. Thefiltrate was concentrated to affordrac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.051 g) as a paleyellow syrup. The crude product was carried forward without furtherpurification. MS (ESI, pos. ion) m/z 240 [M+1].

Step 6. rac-6-bromo-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline(Intermediate 6)

A 50-mL round bottomed flask equipped with a magnetic stir bar andthermocouple was charged withrac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.574 g, 2.399 mmol)and acetonitrile (11.5 mL). The solution was cooled to 0° C., andN-bromosuccinimide (0.427 g, 2.399 mmol) was added in one portion. Thesolution turned yellow, and the internal temperature rose to 5° C.before falling back to 0° C. After 10 min, additional N-bromosuccinimide(0.021 g, 0.120 mmol) was added. After an additional 10 min, thereaction mixture was removed from the ice bath and concentrated underreduced pressure. The residue was then partitioned between ethyl acetateand 10% aqueous sodium carbonate solution. The layers were separated,and the ethyl acetate layer was washed with 5% aqueous sodium chloridesolution (10 mL) and concentrated to a yellow oil (0.81 g). The crudeproduct was purified by column chromatography on silica gel (elutingwith 12:1 hexanes-ethyl acetate followed by 10:1 hexanes-ethyl acetate)to afford rac-6-bromo-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline(0.60, 79%) as a colorless syrup. MS (ESI, pos. ion) m/z 318, 320 [M+1].

Example 7 Intermediate7—3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thietane1,1-dioxide

A 100-mL round bottomed flask was charged with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.942 g,4.85 mmol), N,N-dimethylformamide (20 mL) and cesium carbonate (3.16 g,9.71 mmol). 3-Bromothietane 1,1-dioxide (0.925 g, 5.00 mmol) was added,and the reaction stirred at 60° C. overnight. The reaction mixture wascooled to room temperature and then partitioned between ethyl acetateand water. The aqueous phase was separated and extracted with ethtylacetate. The combined organic phases were washed with water and brineand concentrated to afford an oil. This material was purified via columnchromatography on silica gel (eluting with 1:5 ethyl acetate-hexanes) toafford3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thietane1,1-dioxide (0.172 g, 12% yield) as a white solid. MS (ESI, pos. ion)m/z 299 [M+H]+.

Example 8 Intermediate8—3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran1,1-dioxide

3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran1,1-dioxide was synthesized from4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and4-bromotetrahydro-2H-thiopyran 1,1-dioxide according to the procedureoutlined above for3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thietane1,1-dioxide (Intermediate 7). ¹³C NMR (400 MHz, CDCl₃) δ ppm 20.85 (s,1C), 24.75 (s, 1C), 24.77 (s, 4C), 31.38 (s, 1C), 50.50 (s, 1C), 56.62(s, 1C), 57.33 (s, 1C), 83.50 (s, 2C), 134.95 (s, 1C), 146.21 (s, 1C).MS (ESI, pos. ion) m/z 327 [M+H]+.

Example 9 Intermediate 9—8-fluoro-5-methoxy-2-methylquinoline

8-Fluoro-5-methoxy-2-methylquinoline was synthesized from2-fluoro-5-methoxyaniline (30.0 g, 213 mmol) according to the proceduresdescribed above for 8-chloro-5-methoxy-2-methylquinoline hydrochloride(Intermediate 1, Step 1) with the following change: The hydrochloridesalt was dissolved in dichloromethane (400 mL) and the pH of theresulting solution was adjusted to 8-9 with saturated aqueous potassiumcarbonate solution. The resulting mixture was extracted withdichloromethane, and the combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith 20% ethyl acetate-petroleum ether) to afford8-fluoro-5-methoxy-2-methylquinoline (25.2 g, 62%) as a yellow solid. MS(ESI, pos. ion) m/z 192[M+H]⁺.

Example 10 Intermediate10—(S)-8-fluoro-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline

(S)-8-Fluoro-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline wassynthesized from 8-fluoro-5-methoxy-2-methylquinoline according to theprocedures described above for(2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (Intermediate 1). MS(ESI, pos. ion) m/z 196[M+H]⁺.

Example 11 Intermediate11—(S)-(6-bromo-8-fluoro-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

(S)-(6-Bromo-8-fluoro-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanonewas synthesized from(S)-8-fluoro-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline according tothe procedures described above for(2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol(Intermediate 2, Steps 1a, 2a, and 3). MS (ESI, pos. ion) m/z 328,330[M+H]⁺.

The following intermediates were prepared according to the proceduredescribed above for Intermediate 11:

Example 12 Intermediate12—(S)-1-(6-bromo-8-fluoro-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

MS (ESI, pos. ion) m/z 302, 304[M+H]⁺.

Example 13 Intermediate 13—(S)-methyl6-bromo-8-fluoro-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

MS (ESI, pos. ion) m/z 318, 320[M+H]⁺.

Example 14 Intermediate14—(S)-1-(6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Step 1. (3,4-difluorophenoxy)triisopropylsilane

Triisopropylsilyl chloride (166 mL, 961.5 mmol) was slowly added to amixture of 3,4-difluorophenol (125 g, 961.5 mmol) and imidazole (65.4 g,961.5 mmol) in N,N-dimethylformamide (500 mL), and the resultingsolution stirred overnight at room temperature. The reaction mixture wasdiluted with water (1500 mL) and extracted with dichloromethane (3×300mL). The combined organic layers washed with water (3×200 mL) and brine(2×200 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with petroleum ether) to afford(3,4-difluorophenoxy)triisopropylsilane (220 g, 80%) as a colorless oil.

Step 2. 2,3-difluoro-5-(triisopropylsilyloxy)benzoic acid

A solution of N,N,N′,N″,N″-pentamethyldiethylenetriamine (60.4 g, 349.1mmol) in tetrahydrofuran (480 mL) was cooled to −70° C., ands-butyllithium (1.25 M in cyclohexane, 335 mL, 419 mmol) was added over10 min. (3,4-Difluorophenoxy)triisopropylsilane (99.85 g, 349.1 mmol)was added dropwise over 1 h, and the resulting mixture stirred for 2 at−70° C. Carbon dioxide was bubbled into the solution, and the resultingmixture stirred for 5 h at −70° C. and then 2 h at room temperature. Thereaction mixture was then poured into water (200 mL), and the pH wasadjusted to 5 with 2 N hydrochloric acid. The resulting mixture wasextracted with ethyl acetate (3×500 mL), and the combined organic layerswere washed with brine (200 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to afford2,3-difluoro-5-(triisopropylsilyloxy)benzoic acid (99.1 g, 86%) as alight yellow solid. MS (ESI, neg. anion) m/z 329[M−H]⁻.

Step 3. 2,3-difluoro-5-hydroxybenzoic acid

Tetrabutylammonium fluoride trihydrate (191 g, 731.8 mmol) was added inportions to a solution of 2,3-difluoro-5-(triisopropylsilyloxy)benzoicacid (99.13 g, 300.0 mmol) in tetrahydrofuran (500 mL), and theresulting mixture stirred overnight at room temperature. The reactionmixture was poured into water (1000 mL) and extracted with ethyl acetate(2×500 mL). The combined organic layers were washed with brine (2×500mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum to afford 2,3-difluoro-5-hydroxybenzoic acid (50 g, 95%) asa light yellow solid. MS (ESI, neg. anion) m/z 173[M−H]⁻.

Step 4. cyclobutyl 5-cyclobutoxy-2,3-difluorobenzoate

Bromocyclobutane (150 g, 1.12 mol) was added to a mixture of2,3-difluoro-5-hydroxybenzoic acid (50 g, 287 mmol), and potassiumcarbonate (230 g, 1.67 mol) in acetonitrile (1500 mL), and the resultingmixture stirred overnight at 90° C. The reaction mixture was cooled toroom temperature, filtered, and concentrated under vacuum. The residuewas purified via column chromatography on silica gel (eluting withpetroleum ether) to afford cyclobutyl 5-cyclobutoxy-2,3-difluorobenzoate(49 g, 60%) as a yellow green solid. MS (ESI, pos. ion) m/z 283 [M+H]⁺.

Step 5. 5-cyclobutoxy-2,3-difluorobenzoic acid

A mixture of cyclobutyl 5-cyclobutoxy-2,3-difluorobenzoate (49 g, 174mmol), ethanol (300 mL), sodium hydroxide (20 g, 500 mmol) and water(300 mL) stirred at 60° C. overnight. The mixture was cooled to roomtemperature and extracted with petroleum ether (2×100 mL). The pH of theaqueous layer was adjusted to 5 with 6 M hydrochloric acid, and then itwas extracted ethyl acetate (3×300 mL). The combined ethyl acetatelayers were washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated to afford 5-cyclobutoxy-2,3-difluorobenzoicacid (38 g, 96%) as a white solid. MS (ESI, neg. anion) m/z 227[M−H]⁻.

Step 6. tert-butyl 5-cyclobutoxy-2,3-difluorophenylcarbamate

A solution of 5-cyclobutoxy-2,3-difluorobenzoic acid (38 g, 148 mmol),t-butanol (280 mL), triethylamine (21.4 mL, 154 mmol) anddiphenylphosphoryl azide (33.2 mL, 154 mmol) stirred overnight at 90° C.The reaction mixture was cooled to room temperature and concentrated.The residue was dissolved dichloromethane (200 mL), washed with 1 Msodium hydroxide (2×100 mL) and brine (2×50 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified viacolumn chromatography on silica gel (eluting with 5% ethylacetate/petroleum ether) to afford tert-butyl5-cyclobutoxy-2,3-difluorophenylcarbamate (32 g, 76%) as a white solid.MS (ESI, pos. ion) m/z 230[M+H]⁺.

Step 7. 5-cyclobutoxy-2,3-difluoroaniline hydrogen chloride

Trifluoroacetic acid (70 mL) was added to a solution of tert-butyl5-cyclobutoxy-2,3-difluorophenylcarbamate (32 g, 107 mmol) indichloromethane (320 mL), and the resulting solution stirred overnightat room temperature. The reaction solution was concentrated, and theresidue was dissolved in dichloromethane (500 mL). A solution of HCl (4M in 1,4-dioxane, 120 mL) was slowly added with stirring. The resultingmixture was concentrated and poured into ethyl ether (480 mL). Theresulting precipitate was filtered, and the filter cake was dried underreduced pressure to afford 5-cyclobutoxy-2,3-difluoroaniline hydrogenchloride (21 g, 89%) as a light yellow solid. MS (ESI, pos. ion) m/z 200[M+H]⁺.

Step 8. 5-cyclobutoxy-7,8-difluoro-2-methylquinoline hydrochloride

A mixture of 5-cyclobutoxy-2,3-difluorobenzenamine hydrogen chloride(9.9 g, 42.1 mmol), concentrated hydrochloric acid (36 mL), chloranil(12.32 g, 49.8 mmol) in n-butanol (60 mL) stirred for 1 h at 100° C.(E)-Crotonaldehyde (19.8 mL, 239 mmol) was added dropwise, and theresulting solution stirred for 1 h at 100° C. and was then cooled to 70°C. Tetrahydrofuran (600 mL) was added, and the mixture stirred foranother 30 min at 70° C. The reaction mixture was cooled to roomtemperature and concentrated under vacuum. The residue was poured intowater (300 mL) and the pH of the mixture was adjusted to 7-8 withsaturated aqueous potassium carbonate solution. The resulting mixturewas extracted with ethyl acetate (3×300 mL), and the combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with 25% ethyl acetate/petroleumether) to afford 5-cyclobutoxy-7,8-difluoro-2-methylquinolinehydrochloride (6 g, 57%) as a yellow solid. MS (ESI, pos. ion) m/z 250[M+H]⁺.

Step 9.(S)-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline

A 30-mL glass-lined stainless steel reactor was charged with5-cyclobutoxy-7,8-difluoro-2-methylquinoline (4.2 g, 16.9 mmol),Cp*Ru(OTf)[(S,S)-TsDPEN](0.100 g, 0.13 mmol) and methanol (10 mL). Thereactor was closed and hydrogen was introduced in at a pressure of 50atm, before being reduced to 1 atm. After this procedure was repeatedthree times, the reactor was pressurized with hydrogen to 50 atm. Theresulting mixture was stirred under this hydrogen pressure for 24 h atroom temperature. After carefully releasing the hydrogen, the reactionmixture was concentrated under vacuum. The residue purified via columnchromatography on silica gel (eluting with 25% ethyl acetate/petroleumether) to afford(S)-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.4g, 33%, 87% ee) as colorless oil.

MS (ESI, pos. ion) m/z 254 [M+H]⁺.

Step 10.(S)-6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline

A solution of N-bromosuccinimide (0.703 g, 3.95 mmol) in acetonitrile(10 mL) was added dropwise to a −5° C. solution of(S)-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.0g, 3.95 mmol) in acetonitrile (80 mL) and dichloromethane (15 mL), andthe resulting solution stirred for 4 h at −5° C. The reaction mixturewas concentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with 50% ethyl acetate/petroleumether) to afford(S)-6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline(1.05 g, 81%) as a yellow solid. MS (ESI, pos. ion) m/z 332,334 [M+H]⁺.

Step 11.(S)-1-(6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Acetyl chloride (0.21 mL, 3.02 mmol) was added dropwise to a 0° C.solution of(S)-6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline(1.0 g, 3.02 mmol) in dichloromethane (20 mL) and pyridine (0.6 mL), andthe resulting solution was allowed to stir and warm to room temperatureovernight. The reaction mixture was diluted with dichloromethane (40mL), washed with 1 N hydrochloric acid (40 mL) and brine (40 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to afford(S)-1-(6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(1.19 g, 99%) as yellow oil. MS (ESI, pos. ion) m/z 374,376[M+H]⁺.

Example 15 Intermediate 15—tert-butyl4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate

Step 1. tert-butyl4-(1H-imidazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of 2-bromo-1H-imidazole (1.2 g, 8.16 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(3.0 g, 9.70 mmol), sodium carbonate (2.1 g, 19.8 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.120 g, 0.16 mmol) in 1,4-dioxane (30 mL) andwater (10 mL) stirred overnight at 100° C. The reaction mixture wascooled to room temperature, poured into ethyl acetate (100 mL), washedwith water (30 mL) and brine (30 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified via column chromatography on silica gel (eluting with 25% ethylacetate-petroleum ether) to afford tert-butyl4-(1H-imidazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.300 g,15%) as a light yellow solid. MS (ESI, pos. ion) m/z 250 [M+H]⁺.

Step 2. tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate

Palladium on carbon (10 wt %, 0.100 g) was added to a solutiontert-butyl 4-(1H-imidazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.300 g, 1.20 mmol) in ethanol (20 mL), and the mixture stirred under ahydrogen atmosphere at room temperature for 2 h. The reaction mixturewas filtered, and the filtrate was concentrated under vacuum to affordtert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (0.300 g, 99%)as an off-white solid. MS (ESI, pos. ion) m/z 252 [M+H]⁺.

Step 3. tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate

A 100-mL round-bottom flask was charged with tert-butyl4-(1H-imidazol-2-yl)piperidine-1-carboxylate (0.300 g, 1.19 mmol) andtetrahydrofuran (10 mL), and the solution was cooled to −78.N-Bromosuccinimide (0.185 g, 1.04 mmol) was added, and the resultingsolution stirred at −78° C. for 2 h. The reaction mixture was pouredinto water (10 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic layers were washed with brine (10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith 2:1, ethyl acetate/petroleum ether) to afford tert-butyl4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (0.26 g, 66%) as awhite solid. MS (ESI, pos. ion) m/z 330, 332 [M+H]⁺.

Example 16 Intermediate 16—tert-butyl4-(4-bromo-1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate

tert-Butyl 4-(4-bromo-1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylatewas synthesized according to the procedure described above fortert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (Intermediate15), substituting 2-bromo-1-methyl-1H-imidazole for 2-bromo-1H-imidazolein Step 1. MS (ESI, pos. ion) m/z 264 [M+H]⁺.

Example 17 Intermediates 17 and 18—tert-butyl4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate 17)and tert-butyl 4-(5-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate 18)

Step 1. tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate

Methanesulfonyl chloride (2.90 mL, 37.6 mmol) was added to a 0° C.solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g, 24.8mmol) and triethyl amine (10.4 mL, 74.65 mmol) in dichloromethane (50mL), and the resulting solution stirred for 1 h at room temperature. Thereaction mixture was diluted with dichloromethane (200 mL), washed withwater (2×50 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to afford tert-butyl4-(methylsulfonyloxy)piperidine-1-carboxylate (7.00 g, 99%) as a yellowsolid. MS (ESI, pos. ion) m/z 280 [M+H]⁺.

Step 2. tert-butyl 4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate 17) and tert-butyl4-(5-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate 18)

A mixture of tert-butyl 4-(methyl sulfonyloxy)piperidine-1-carboxylate(0.837 g, 3.00 mmol), 3-bromo-1H-pyrazole (0.441 g, 3.02 mmol), andcesium carbonate (2.94 g, 9.02 mmol) in DMF (10 mL) stirred for 5 h at100° C. The reaction mixture was cooled to room temperature and pouredethyl acetate (50 mL). The mixture was washed with water (3×10 mL),dried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue purified via column chromatography on silica gel(eluting with 10% dichloromethane/methanol to afford tert-butyl4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.25 g, 25%) as awhite solid. MS (ESI, pos. ion) m/z 330,332 [M+H]⁺.

tert-butyl 4-(5-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.150 g,15%) was also obtained as a white solid. MS (ESI, pos. ion) m/z 330,332[M+H]⁺.

Example 18 Intermediates 19 and 20—tert-butyl4-(4-bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (Intermediate19) and tert-butyl4-(4-bromo-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (Intermediate20)

Step 1. 4,5-dibromo-2H-1,2,3-triazole

Bromine (11.59 g, 73.35 mmol) was added dropwise to a 0° C. solution of2H-1,2,3-triazole (5.00 g, 72.46 mmol) in water (50 mL), and theresulting solution was allowed to warm to room temperature and stirovernight. The precipitate was collected by filtration and dried toafford 4,5-dibromo-2H-1,2,3-triazole (8.00 g, 49%) as a white solid. MS(ESI, pos. ion) m/z 228, 226, 230 [M+H]⁺.

Step 2. tert-butyl4-(4,5-dibromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate andtert-butyl 4-(4,5-dibromo-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

A mixture of 4,5-dibromo-2H-1,2,3-triazole (2.27 g, 10.08 mmol),tert-butyl 4-(methyl sulfonyloxy)piperidine-1-carboxylate (2.79 g, 10.00mmol), and cesium carbonate (9.75 g, 29.91 mmol) inN,N-dimethylformamide (50 mL) stirred overnight at 100° C. The reactionmixture was cooled to room temperature, poured into water (100 mL) andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (100 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to afford a mixture of tert-butyl4-(4,5-dibromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate andtert-butyl 4-(4,5-dibromo-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate(4.00 g, 97%) as a yellow oil. MS (ESI, pos. ion) m/z 411, 409, 413[M+H]⁺.

Step 3. tert-butyl4-(4-bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (Intermediate19) and tert-butyl4-(4-bromo-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (Intermediate20)

n-Butyllithium (2.5 M in hexanes, 2.92 mL, 7.30 mmol) was added dropwiseto a −78° C. solution containing a mixture of tert-butyl4-(4,5-dibromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate andtert-butyl 4-(4,5-dibromo-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate(3.00 g, 7.35 mmol) in tetrahydrofuran (20 mL). The resulting solutionstirred for 1 hour at −78° C., and then the reaction mixture was pouredinto saturated aqueous ammonium chloride solution (20 mL). The aqueousphase was separated and extracted with ethyl acetate (3×20 mL), and thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (eluting with 2:1, ethylacetate/petroleum ether) to afford tert-butyl4-(4-bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (0.800 g, 33%)as a colorless oil. MS (ESI, pos. ion) m/z 331, 333[M+H]⁺.

tert-Butyl 4-(4-bromo-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate(0.500 g, 20%) was also obtained as a colorless oil. MS (ESI, pos. ion)m/z 331, 333 [M+H]⁺.

Example 19 Intermediate 21—tert-butyl3-(4-bromothiazol-2-yl)azetidine-1-carboxylate

1,2-Dibromoethane (0.084 mL, 0.97 mmol) was added to a mixture of zincpowder (0.520 g, 8.13 mmol) in tetrahydrofuran (2 mL), and the resultingmixture was stirred for 10 min at 80° C. and was then cooled to roomtemperature. A solution of chlorotrimethylsilane (0.115 mL, 1.22 mmol)in tetrahydrofuran (1 mL) was added dropwise with stirring, and theresulting mixture stirred for 45 min at room temperature. A solution oftert-butyl 3-iodoazetidine-1-carboxylate (1.74 g, 6.15 mmol) intetrahydrofuran (2 mL) was added, and the resulting mixture stirred for2 h at room temperature. A solution of 2,4-dibromothiazole (0.744 g,3.09 mmol) in tetrahydrofuran (1 mL) andtetrakis(triphenylphosphine)palladium(0) (0.354 g, 0.31 mmol) wereadded, and the resulting mixture stirred overnight at room temperature.The reaction mixture was poured into water (10 mL) and extracted withethyl acetate (3×10 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith 1:2, ethyl acetate/petroleum ether) to afford tert-butyl3-(4-bromothiazol-2-yl)azetidine-1-carboxylate (0.151 g, 8%) of asyellow oil. MS (ESI, pos. ion) m/z 319,321 [M+H]⁺.

Example 20 Intermediate 22—tert-butyl3-(4-bromothiazol-2-yl)-3-hydroxyazetidine-1-carboxylate

n-Butyllithium (1.6 M in THF, 6.3 mL, 10.1 mmol) was added dropwise to a−78° C. solution of 2,4-dibromothiazole (2.00 g, 8.30 mmol) intetrahydrofuran (50 mL), and the mixture stirred at −78° C. for 1 h. Asolution of tert-butyl 3-oxoazetidine-1-carboxylate (2.83 g, 16.55 mmol)in tetrahydrofuran (5 mL) was added, and the resulting mixture stirredfor 1 h at room temperature. The reaction mixture was poured intosaturated aqueous ammonium chloride solution (50 mL) and extracted withdichloromethane (3×50 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith 20% with ethyl acetate/petroleum ether) to afford tert-butyl3-(4-bromothiazol-2-yl)-3-hydroxyazetidine-1-carboxylate (0.890 g, 32%)as a white solid. MS (ESI, pos. ion) m/z 335, 337 [M+H]⁺.

Example 21 Intermediate 23—N-(4-bromothiazol-2-yl)acetamide

A solution of 4-bromothiazol-2-amine (0.500 g, 2.81 mmol), aceticanhydride (0.43 mL, 4.50 mmol) and acetic acid (5 mL) was refluxed for 2h. The reaction mixture was cooled to room temperature and concentratedunder vacuum. The residue was purified via column chromatography onsilica gel (eluting with 25% ethyl acetate-petroleum ether) to affordN-(4-bromothiazol-2-yl)acetamide (0.300 g, 49%) as a white solid. MS(ESI, pos. ion) m/z 221, 223 [M+H]⁺.

Example 22 Intermediate 24—N-(4-bromothiazol-2-yl)acetamide

Into a 100-mL round-bottom flask, was placed4-bromothiazole-2-carboxylic acid (800 mg, 3.86 mmol, 1.00 equiv), DIEA(1.03 g, 7.92 mmol, 2.00 equiv), tetrahydrofuran (50 mL), NH₄Cl (424 mg,8.00 mmol, 2.07 equiv) and HATU (1.82 g, 4.80 mmol, 1.24 equiv). Theresulting mixture was stirred for 24 h at 25° C. The reaction mixturewas concentrated under vacuum, dissolved in 25 mL of ethyl acetate,washed with 3×5 mL of water, 5 mL of brine, dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1/1). Thisresulted in 500 mg (63%) of 4-bromothiazole-2-carboxamide as a whitesolid. MS (ESI, pos. ion) m/z 207, 209 [M+H]⁺.

Example 23 Intermediate 25—4-bromo-N-methylthiazole-2-carboxamide

4-Bromo-N-methylthiazole-2-carboxamide was synthesized according to theprocedure described above for N-(4-bromothiazol-2-yl)acetamide(Intermediate 24), substituting methyl amine for ammonium chloride. MS(ESI, pos. ion) m/z 221, 223 [M+H]⁺.

Example 24(S)-1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-1)

Step 1.(S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.150 g, 0.528 mmol), 1-bromopropane (0.24 mL, 2.64 mmol), andpotassium tert-butoxide (0.296 g, 2.64 mmol) in N,N-dimethylformamide(3.0 mL) was heated at 80° C. After 24 h, a second portion of1-bromopropane (0.24 mL, 2.64 mmol) and potassium tert-butoxide (0.296g, 2.64 mmol) was added and the mixture was heated at 100° C. for 24 h.The reaction mixture was cooled to rt and water was added. The mixturewas extracted with dichloromethane and the combined organic phases werewashed with water and brine, dried over anhydrous sodium sulfate,filtered, and concentrated to afford a yellow oil. This material waspurified via column chromatography on silica gel (Biotage 25 g column,gradient elution with 50-100% ethyl acetate-hexane) to afford(S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.100 g, 58%) as a colorless oil. MS (ESI, pos. ion) m/z 326, 328[M+H]⁺.

Step 2.(S)-1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of(S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.050 g, 0.153 mmol),2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol(0.055 g, 0.230 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (XPhos 2nd generation precatalyst) (0.012 g, 0.015 mmol),and cesium carbonate (0.150 g, 0.460 mmol) in 1,4-dioxane (2.0 mL) andwater (0.40 mL) was heated in the microwave at 100° C. for 2.5 h. Thereaction mixture was filtered through Celite and concentrated to affordan orange oil. This material was purified via column chromatography onsilica gel (Biotage 25 g column, gradient elution with 50-100% ethylacetate-hexane followed by 10% methanol-ethyl acetate) to afford(S)-1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.047 g, 86%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.97 (t, J=7.48 Hz, 3H), 1.03 (d, J=6.45 Hz, 3H), 1.23 (m, 1H),1.64-1.80 (m, 2H), 2.07 (s, 3H), 2.18-2.38 (m, 2H), 2.75-2.90 (m, 1H),3.50-3.65 (m, 2H), 3.68-3.80 (m, 2H), 4.17 (t, J=5.57 Hz, 2H), 4.62 (m,1H), 4.84-4.94 (m, 1H), 7.12 (br d, J=8.21 Hz, 1H), 7.38 (d, J=8.50 Hz,1H), 7.85 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion) m/z 358 [M+H]⁺.

The following examples were made according to the procedure outlined forExample 24:

(S)-2-(1-acetyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-N,N-dimethylacetamide(I-2)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.98-1.09 (m, 3H), 1.29 (m, 1H), 2.08(s, 3H), 2.18-2.40 (m, 1H), 2.75-2.90 (m, 2H), 2.81 (s, 3H), 2.84 (s,3H), 3.63-3.78 (m, 2H), 4.05-4.18 (m, 2H), 4.22-4.48 (m, 2H), 4.61 (m,1H), 4.82-4.95 (m, 1H), 7.15 (br d, J=8.50 Hz, 1H), 7.43 (d, J=8.50 Hz,1H), 7.93 (s, 1H), 8.21 (s, 1H). MS (ESI, pos. ion) m/z 401 [M+H]⁺.

(S)-methyl5-(2-(dimethylamino)-2-oxoethoxy)-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-3)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.03-1.12 (m, 3H), 1.48 (td, J=13.12,6.89 Hz, 1H), 2.09 (td, J=13.63, 5.28 Hz, 1H), 2.70-2.82 (m, 2H), 2.80(s, 3H), 2.84 (s, 3H), 3.67 (s, 3H), 3.72 (q, J=5.77 Hz, 2H), 4.11 (t,J=5.57 Hz, 2H), 4.35 (q, J=13.88 Hz, 2H), 4.42-4.56 (m, 1H), 4.88 (t,J=5.28 Hz, 1H), 7.23-7.34 (m, 1H), 7.35-7.45 (m, 1H), 7.90 (s, 1H), 8.18(s, 1H). MS (ESI, pos. ion) m/z 417 [M+H]⁺.

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-N-ethylacetamide(I-4)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.15 (m, 7H), 1.22 (t, J=7.20 Hz,3H), 1.29-1.42 (m, 1H), 2.17 (s, 3H), 2.31-2.45 (m, 2H), 2.91-3.01 (m,1H), 3.35-3.43 (m, 3H), 3.65-3.72 (m, 1H), 4.07 (d, J=14.40 Hz, 1H),4.15 (d, J=14.40 Hz, 1H), 4.71-4.81 (m, 1H), 7.08-7.15 (m, 1H), 7.43 (d,J=8.40 Hz, 1H), 7.89 (s, 1H), 8.12 (s, 1H). MS (ESI, pos. ion) m/z 397[M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoroethoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-5)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.15 (m, 7H), 1.21-1.39 (m, 1H), 2.15(s, 3H), 2.22-2.43 (m, 2H), 2.95-2.07 (m, 1H), 3.63-3.71 (m, 1H),3.81-4.01 (m, 2H), 4.50-4.62 (m, 1H), 4.67-4.78 (m, 2H), 7.02-7.13 (m,1H), 7.45 (d, J=8.40 Hz, 1H), 7.89 (s, 1H), 8.12 (s, 1H). MS (ESI, pos.ion) m/z 358 [M+H]⁺.

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-N-cyclopropyl-N-methylacetamide(I-6)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.55-0.65 (m, 2H), 0.72-0.78 (m, 2H),1.05-1.15 (m, 7H), 1.23-1.41 (m, 1H), 2.19 (s, 3H), 2.30-2.42 (m, 2H),2.51-2.59 (m, 1H), 2.98 (s, 3H), 2.95-3.08 (m, 1H), 3.65-3.72 (m, 1H),4.55 (d, J=14.80 Hz, 1H), 4.64 (d, J=14.80 Hz, 1H), 4.71-4.83 (m, 1H),7.05-7.20 (m, 1H), 7.47 (d, J=8.40 Hz, 1H), 7.91 (s, 1H), 8.21 (s, 1H).MS (ESI, pos. ion) m/z 423 [M+H]⁺.

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-1-(azetidin-1-yl)ethanone(I-7)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.02-1.15 (m, 7H), 1.24-1.43 (m, 1H), 2.16(s, 3H), 2.24-2.43 (m, 4H), 2.90-3.05 (m, 1H), 3.65-3.75 (m, 1H),4.01-4.25 (m, 6H), 4.65-4.82 (m, 1H), 7.05-7.15 (m, 1H), 7.45 (d, J=8.10Hz, 1H), 7.89 (s, 1H), 8.19 (s, 1H). MS (ESI, pos. ion) m/z 409 [M+H]⁺.

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-1-(piperidin-1-yl)ethanone(I-8)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.18 (m, 7H), 1.21-1.53 (m, 3H),1.55-1.73 (m, 4H), 2.18 (s, 3H), 2.30-2.47 (m, 2H), 2.94-3.05 (m, 1H),3.21-3.38 (m, 2H), 3.58-3.65 (m, 2H), 3.66-3.74 (m, 1H), 4.39 (d,J=14.10 Hz, 1H), 4.50 (d, J=14.10 Hz, 1H), 4.73-4.85 (m, 1H), 7.09-7.17(m, 1H), 7.48 (d, J=8.40 Hz, 1H), 7.92 (s, 1H), 8.21 (s, 1H). MS (ESI,pos. ion) m/z 437 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2,2,2-trifluoroethoxy)-3,4-dihydroquinoline-1(2H)-carboxylate(I-9)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.19 (m, 7H), 1.49-1.68 (m, 1H),2.14-2.28 (m, 1H), 2.50-2.63 (m, 1H), 2.87-3.01 (m, 1H), 3.65-3.78 (m,1H), 3.78 (s, 3H), 4.01-4.18 (m, 2H), 4.55-4.68 (m, 1H), 7.37 (q, d=8.70Hz, 2H), 7.83 (s, 1H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z 410 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoroethoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-10)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.01-1.20 (m, 7H), 1.50-1.62 (m, 1H),2.20-2.28 (m, 1H), 2.49-2.59 (m, 1H), 2.91-3.01 (m, 1H), 3.67-3.72 (m,1H), 3.79 (s, 3H), 3.79-3.91 (m, 2H), 4.55-4.62 (m, 1H), 6.10 (tt,J=54.80, 3.60 Hz, 1H), 7.37 (s, 2H), 7.86 (s, 1H), 8.04 (s, 1H). MS(ESI, pos. ion) m/z 392 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoroethoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-11)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.01-1.15 (m, 4H), 1.18 (d, J=6.80 Hz,3H), 1.47-1.58 (m, 1H), 2.18-2.25 (m, 1H), 2.48-2.58 (m, 1H), 2.90-2.99(m, 1H), 3.63-3.71 (m, 1H), 3.78 (s, 3H), 3.81-3.87 (m, 1H), 3.90-3.94(m, 1H0, 4.51-4.62 (m, 2H), 4.68-4.73 (m, 1H), 7.33 (d, J=8.40 Hz, 1H),7.38 (d, J=8.80 Hz, 1H), 7.88 (s, 1H), 8.11 (s, 1H). MS (ESI, pos. ion)m/z 374 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoropropoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-12)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.02-1.19 (m, 7H), 1.51-1.62 (m, 1H), 1.77(t, J=18.90 Hz, 3H), 2.15-2.25 (m, 1H), 2.51-2.68 (m, 1H), 2.89-3.01 (m,1H), 3.65-3.71 (m, 1H), 3.75-3.85 (m, 5H), 4.55-4.65 (m, 1H), 7.36-7.37(m, 2H), 7.86 (s, 1H), 8.06 (s, 1H). MS (ESI, pos. ion) m/z 406 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3,3,3-trifluoropropoxy)-3,4-dihydroquinoline-1(2H)-carboxylate(I-13)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.19 (m, 7H), 1.48-1.61 (m, 1H),2.15-2.27 (m, 1H), 2.48-2.72 (m, 3H), 2.85-2.95 (m, 1H), 3.65-3.72 (m,1H), 3.72-3.83 (m, 5H), 4.58-4.62 (m, 1H), 7.28-7.34 (m, 2H), 7.82 (s,1H), 8.01 (s, 1H). MS (ESI, pos. ion) m/z 424 [M+H]⁺.

(S)-methyl5-(2-amino-1,1-difluoro-2-oxoethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-14)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.98-1.21 (m, 7H), 1.25-1.39 (m, 1H),2.21-2.45 (m, 2H), 2.91-3.04 (m, 1H), 3.61-3.68 (m, 1H), 3.77 (s, 3H),4.41-4.52 (m, 1H), 7.37-7.41 (m, 2H), 7.79 (s, 1H), 8.05 (s, 1H). MS(ESI, pos. ion) m/z 421 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1,3-difluoropropan-2-yloxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-15)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.98-1.15 (m, 4H), 1.18 (d, J=6.60 Hz,3H), 1.35-1.45 (m, 1H), 2.20-2.31 (m, 1H), 2.35-2.47 (m, 1H), 2.95-3.03(m, 1H), 3.62-3.69 (m, 1H), 3.69 (s, 3H), 4.05-4.25 (m, 1H), 4.29-4.33(m, 1H), 4.45-4.52 (m, 3H), 4.61-4.63 (m, 1H), 7.31 (s, 2H), 7.78 (s,1H), 7.99 (s, 1H). MS (ESI, pos. ion) m/z 406 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-2-methylpropoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-16)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.98-1.18 (m, 7H), 1.37-1.62 (m, 7H),2.11-2.23 (m, 1H), 2.48-2.59 (m, 1H), 2.87-2.99 (m, 1H), 3.57 (s, 1H),3.58-3.71 (m, 2H), 3.77 (s, 3H), 4.52-4.62 (m, 1H), 7.28-7.29 (m, 2H),7.86 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion) m/z 402 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-17)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.99 (s, 6H), 1.01-1.18 (m, 7H), 1.45-1.61(m, 1H), 2.17-2.23 (m, 1H), 2.47-2.57 (m, 1H), 2.91-3.01 (m, 1H),3.30-3.45 (m, 4H), 3.60-3.71 (m, 1H), 3.77 (s, 3H), 4.51-4.62 (m, 1H),7.19-7.30 (m, 2H), 7.76 (s, 1H), 7.98 (s, 1H). MS (ESI, pos. ion) m/z414 [M+H]⁺.

(S)-methyl5-(1-amino-2-methyl-1-oxopropan-2-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-18)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.98-1.38 (m, 14H), 2.20-2.39 (m, 2H),2.92-3.03 (m, 1H), 3.63-3.72 (m, 1H), 3.77 (s, 3H), 4.38-4.52 (m, 1H),7.18-7.28 (m, 2H), 7.72 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z413 [M+H]⁺.

(S)-methyl5-((R)-2-amino-1-fluoro-2-oxoethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-19)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.34 (m, 7H), 1.42-1.58 (m, 1H),2.15-2.29 (m, 1H), 2.48-2.62 (m, 1H), 2.95-3.09 (m, 1H), 3.59-3.71 (m,1H), 3.79 (s, 3H), 4.52-4.63 (m, 1H), 5.41 (d, J=61.20 Hz, 1H), 7.38 (d,J=8.70 Hz, 1H), 7.45 (d, J=8.70 Hz, 1H), 7.83 (s, 1H), 8.08 (s, 1H). MS(ESI, pos. ion) m/z 403 [M+H]⁺. Stereochemistry of fluorine tentativelyassigned.

(S)-methyl5-((S)-2-amino-1-fluoro-2-oxoethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-20)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.03-1.1.35 (m, 7H), 1.45-1.55 (m, 1H),2.17-2.24 (m, 1H), 2.49-2.72 (m, 1H), 3.01-3.12 (m, 1H), 3.68-3.73 (m,1H), 3.80 (s, 3H), 4.55-4.65 (m, 1H), 5.49 (d, J=61.50 Hz, 1H), 7.41 (d,J=8.40 Hz, 1H), 7.47 (d, J=8.70 Hz, 1H), 7.84 (s, 1H), 8.09 (s, 1H). MS(ESI, pos. ion) m/z 403 [M+H]⁺. Stereochemistry of fluorine tentativelyassigned.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-(ethylamino)-2-oxoethoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-21)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.27 (m, 10H), 1.55-1.65 (m, 1H),2.15-2.23 (m, 1H), 2.58-2.68 (m, 1H), 2.83-2.93 (m, 1H), 3.29-3.38 (m,2H), 3.65-3.71 (m, 1H), 3.78 (s, 3H), 4.08 (s, 2H), 4.55-4.65 (m, 1H),7.35-7.42 (m, 2H), 7.86 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion) m/z413 [M+H]⁺.

(S)-methyl5-(2-(cyclopropyl(methyl)amino)-2-oxoethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-22)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.48-0.62 (m, 2H), 0.65-0.83 (m, 2H),1.01-1.09 (m, 4H), 1.17 (d, J=6.30 Hz, 3H), 1.48-1.62 (m, 1H), 2.15-2.25(m, 1H), 2.28-2.63 (m, 2H), 2.78-3.01 (m, 4H), 3.65-3.72 (m, 1H), 3.77(s, 3H), 4.049-4.63 (m, 3H), 7.31-7.41 (m, 2H), 7.87 (s, 1H), 8.12 (s,1H). MS (ESI, pos. ion) m/z 439 [M+H]⁺.

(S)-methyl5-(2-(azetidin-1-yl)-2-oxoethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-23)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.99-1.19 (m, 7H), 1.49-1.62 (m, 1H),2.15-2.35 (m, 3H), 2.49-2.63 (m, 1H), 2.87-2.98 (m, 1H), 3.76-3.82 (m,1H), 3.76 (s, 3H), 4.01-4.20 (m, 6H), 4.58-4.65 (m, 1H), 7.36 (s, 2H),7.86 (s, 1H), 8.12 (s, 1H). MS (ESI, pos. ion) m/z 425 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2-oxo-2-(piperidin-1-yl)ethoxy)-3,4-dihydroquinoline-1(2H)-carboxylate(I-24)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.99-1.12 (m, 4H), 1.17 (d, J=6.60 Hz,3H), 1.38-1.72 (m, 7H), 2.10-2.23 (m, 1H), 2.49-2.62 (m, 1H), 2.85-2.99(m, 1H), 3.17-3.21 (m, 2H), 3.55-3.60 (m, 2H), 3.61-3.68 (m, 1H), 3.76(s, 3H), 4.38 (q, J=14.10 Hz, 2H), 4.51-4.62 (m, 1H), 7.36 (s, 2H), 7.86(s, 1H), 8.12 (s, 1H). MS (ESI, pos. ion) m/z 453 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2-(2-oxopyrrolidin-1-yl)ethoxy)-3,4-dihydroquinoline-1(2H)-carboxylate(I-25)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.19 (m, 7H), 1.48-1.62 (m, 1H),2.03-2.25 (m, 3H), 2.40-2.58 (m, 3H), 2.80-2.91 (m, 1H), 3.50-3.61 (m,4H), 3.68-3.79 (m, 6H), 4.55-4.65 (m, 1H), 7.25-7.32 (m, 2H), 7.80 (s,1H), 8.03 (s, 1H). MS (ESI, pos. ion) m/z 439 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2-morpholino-2-oxoethoxy)-3,4-dihydroquinoline-1(2H)-carboxylate(I-26)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.12 (m, 4H), 1.18 (d, J=6.40 Hz,3H), 1.52-1.63 (m, 1H), 2.17-2.23 (m, 1H), 2.50-2.65 (m, 1H), 2.89-3.01(m, 1H), 3.53-3.73 (m, 7H), 3.78 (s, 3H), 4.31-4.45 (m, 2H), 4.58-4.63(m, 1H), 7.30-7.38 (m, 2H), 7.88 (s, 1H), 8.15 (s, 1H). MS (ESI, pos.ion) m/z 455 [M+H]⁺.

methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[2-(1,1-dioxo-1λ⁶,2-thiazolidin-2-yl)ethoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-27)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.19 (m, 7H), 1.48-1.49 (m, 1H),2.15-2.23 (m, 1H), 2.30-2.41 (m, 2H), 2.48-2.58 (m, 1H), 2.89-3.01 (m,1H), 3.18-3.22 (m, 2H), 3.35-3.41 (m, 4H), 3.63-3.79 (m, 6H), 4.52-4.62(m, 1H), 7.32 (s, 2H), 7.87 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion)m/z 475 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(sulfamoylmethoxy)-3,4-dihydroquinoline-1(2H)-carboxylate(I-28)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.99-1.09 (m, 2H), 1.11-1.19 (m, 5H),1.49-1.62 (m, 1H), 2.15-2.25 (m, 1H), 2.52-2.68 (m, 1H), 2.99-2.3.12 (m,1H), 3.61-3.70 (m, 1H), 3.78 (s, 3H), 4.50-4.63 (m, 3H), 7.39 (s, 2H),7.89 (s, 1H), 8.20 (s, 1H). MS (ESI, pos. ion) m/z 421 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((N,N-dimethylsulfamoyl)methoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-29)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.98-1.19 (m, 7H), 1.52-1.63 (m, 1H),2.15-2.25 (m, 1H), 2.55-2.73 (m, 1H), 2.88-3.02 (m, 7H), 3.60-3.72 (m,1H), 3.77 (s, 3H), 4.50-4.67 (m, 3H), 7.34 (d, J=8.70 Hz, 1H), 7.41 (d,J=8.70 Hz, 1H), 7.85 (s, 1H), 8.12 (s, 1H). MS (ESI, pos. ion) m/z 449[M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2-(oxetan-3-yl)ethoxy)-3,4-dihydroquinoline-1(2H)-carboxylate(I-30)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.19 (m, 7H), 1.45-1.69 (m, 1H),2.03-2.21 (m, 3H), 2.38-2.53 (m, 1H), 2.75-2.89 (m, 1H), 3.15-3.20 (m,1H), 3.47-3.58 (m, 2H), 3.65-3.73 (m, 1H), 3.76 (s, 3H), 4.40-4.48 (m,2H), 4.49-4.62 (m, 1H), 4.78-4.83 (m, 2H), 7.21-7.31 (m, 2H), 7.80 (s,1H), 7.99 (s, 1H). MS (ESI, pos. ion) m/z 412 [M+H]⁺.

(2S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((2,2-difluorocyclopropyl)methoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-31)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.19 (m, 8H), 1.45-1.58 (m, 2H),1.90-2.05 (m, 1H), 2.18-2.25 (m, 1H), 2.45-2.55 (m, 1H), 2.88-2.99 (m,1H), 3.57-3.71 (m, 2H), 3.77 (s, 3H), 3.78-3.83 (m, 1H), 4.50-4.61 (m,1H), 7.32 (s, 2H), 7.84 (s, 1H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z418 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-32)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.17 (m, 7H), 1.45-1.55 (m, 1H),2.15-2.25 (m, 1H), 2.48-2.62 (m, 1H), 2.88-2.99 (m, 1H), 3.67-3.72 (m,1H), 3.75-3.85 (m, 7H), 4.45-4.63 (m, 5H), 7.25 (d, J=8.40 Hz, 1H), 7.33(d, J=8.70 Hz, 1H), 7.73 (s, 1H), 7.93 (s, 1H). MS (ESI, pos. ion) m/z428 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3,3-difluorocyclobutoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-33)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.02-1.19 (m, 7H), 1.38-1.48 (m, 1H),2.25-2.31 (m, 1H), 2.39-2.48 (m, 1H), 2.53-2.82 (m, 4H), 2.89-2.95 (m,1H), 3.68-3.73 (m, 1H), 3.78 (s, 3H), 4.21-4.30 (m, 1H), 4.48-4.58 (m,1H), 7.30 (s, 2H), 7.79 (s, 1H), 7.99 (s, 1H). MS (ESI, pos. ion) m/z418 [M+H]⁺.

tert-butyl(S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate(I-34)

¹H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (t, 3H), 1.00 (d, 3H), 1.20-1.30(m, 2H), 1.40 (s, 9H), 1.59-1.69 (m, 2H), 2.05 (s, 3H), 2.16-2.32 (m,2H), 2.36-2.44 (m, 2H), 2.70-2.81 (m, 1H), 3.49 (d, 2H), 3.53-3.67 (m,2H), 3.94 (t, 2H), 5.82 (m, 1H), 6.98 (d, 1H), 7.07 (d, 1H). MS (ESI,pos. ion) m/z 429 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2,2,2-trifluoroethoxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-35)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.18 (m, 7H), 1.21-1.42 (m, 1H), 2.16(s, 3H), 2.28-2.32 (m, 2H), 2.95-3.05 (m, 1H), 3.65-3.75 (m, 1H),4.01-4.21 (m, 2H), 4.68-4.83 (m, 1H), 7.10-7.20 (m, 1H), 7.43 (d, J=8.10Hz, 1H), 7.85 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 394 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoroethoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-36)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.20 (m, 7H), 1.28-1.43 (m, 1H), 2.18(s, 3H), 2.28-2.35 (m, 2H), 2.95-3.05 (m, 1H), 3.65-3.75 (m, 1H),3.85-4.01 (m, 2H), 4.61 (s, 1H), 4.69-4.82 (m, 1H), 6.13 (tt, J=54.60,3.30 Hz, 1H), 7.05-7.15 (m, 1H), 7.46 (d, J=8.40 Hz, 1H), 7.90 (s, 1H),8.11 (s, 1H). MS (ESI, pos. ion) m/z 376 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoropropoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-37)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.01-1.18 (m, 7H), 1.25-1.40 (m, 1H), 1.77(t, J=18.80 Hz, 3H), 2.18 (s, 3H), 2.30-2.42 (m, 2H), 2.95-3.05 (m, 1H),3.68-3.89 (m, 3H), 4.70-4.82 (m, 1H), 7.05-7.18 (m, 1H), 7.44 (d, J=8.40Hz, 1H), 7.88 (s, 1H), 8.10 (s, 1H). MS (ESI, pos. ion) m/z 390 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1,3-difluoropropan-2-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-38)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.98-1.30 (m, 8H), 2.15 (s, 3H), 2.25-2.49(m, 2H), 3.05-3.12 (m, 1H), 3.65-3.72 (m, 1H), 4.10-4.32 (m, 2H),4.47-4.54 (m, 2H), 4.65-4.80 (m, 2H), 7.05-7.15 (m, 1H), 7.40 (d, J=8.10Hz, 1H), 7.92 (s, 1H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z 390 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-39)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.99 (s, 6H), 1.05-1.25 (m, 7H), 1.23-1.35(m, 1H), 2.17 (s, 3H), 2.23-2.38 (m, 2H), 3.01-3.13 (m, 1H), 3.40-3.48(m, 4H), 3.65-3.75 (m, 1H), 4.70-4.83 (m, 1H), 7.01-7.09 (m, 1H), 7.35(d, J=8.00 Hz, 1H), 7.81 (s, 1H), 8.04 (s, 1H). MS (ESI, pos. ion) m/z398 [M+H]⁺.

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-2-methylpropanamide(I-40)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.98-1.20 (m, 11H), 1.30 (s, 3H),2.05-2.30 (m, 4H), 2.33-2.45 (m, 1H), 3.01-3.12 (m, 1H), 3.65-3.72 (m,1H), 4.60-4.72 (m, 1H), 7.05-7.12 (m, 1H), 7.33 (d, J=8.10 Hz, 1H), 7.77(s, 1H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z 397 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3,3,3-trifluoropropoxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-41)

¹H NMR (400 MHz, CDCl₃) δ ppm 1.07-1.18 (m, 7H), 1.31-1.37 (m, 1H), 2.18(s, 2H), 2.38-2.41 (m, 2H), 2.61-2.72 (m, 2H), 2.97-3.02 (m, 1H),3.69-3.75 (m, 1H), 3.82-3.92 (m, 2H), 4.78 (s, 1H), 7.14 (s, 1H), 7.41(d, J=8.00 Hz, 1H), 7.87 (s, 1H), 8.10 (s, 1H). MS (ESI, pos. ion) m/z408 [M+H]⁺.

(S)-1-(2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)ethyl)pyrrolidin-2-one(I-42)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.19 (m, 7H), 1.25-1.39 (m, 1H),2.01-2.19 (m, 5H), 2.27-2.48 (m, 4H), 2.85-2.95 (m, 1H), 3.55-3.68 (m,4H), 3.59-3.84 (m, 3H), 4.65-4.78 (m, 1H), 7.01-7.12 (m, 1H), 7.37 (d,J=8.40 Hz, 1H), 7.83 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion) m/z 423[M+H]⁺.

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-1-morpholinoethanone(I-43)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.15 (m, 7H), 1.15-1.45 (m, 1H), 2.16(s, 3H), 2.30-2.43 (m, 2H), 2.90-3.05 (m, 1H), 3.50-3.80 (m, 7H),4.35-4.55 (m, 2H), 4.68-4.84 (m, 1H), 7.05-7.15 (m, 1H), 7.46 (d, J=8.40Hz, 1H), 7.90 (s, 1H), 8.19 (s, 1H). MS (ESI, pos. ion) m/z 439 [M+H]⁺.

2-(2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-1λ⁶,2-thiazolidine-1,1-dione(I-44)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.19 (m, 7H), 1.25-1.35 (m, 1H), 2.16(s, 3H), 2.28-2.45 (m, 4H), 2.98-3.05 (m, 1H), 3.22 (t, J=7.80 Hz, 2H),3.28-3.42 (m, 4H), 3.68-3.86 (m, 3H), 4.70-4.83 (m, 1H), 7.05-7.12 (m,1H), 7.41 (d, J=8.40 Hz, 1H), 7.91 (s, 1H), 8.12 (s, 1H). MS (ESI, pos.ion) m/z 459 [M+H]⁺.

(S)-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)methanesulfonamide(I-45)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.01-1.25 (m, 7H), 1.30-1.45 (m, 1H), 2.18(s, 3H), 2.30-2.45 (m, 2H), 3.10-3.20 (m, 1H), 3.68-3.72 (m, 1H),4.58-4.68 (m, 2H), 4.70-4.85 (m, 1H), 7.10-7.20 (m, 1H), 7.47 (d, J=8.40Hz, 1H), 7.93 (s, 1H), 8.21 (s, 1H). MS (ESI, pos. ion) m/z 405 [M+H]⁺.

(S)-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-N,N-dimethylmethanesulfonamide(I-46)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.03-1.23 (m, 7H), 1.34-1.52 (m, 1H), 2.18(s, 3H), 2.30-2.52 (m, 2H), 3.00 (s, 6H), 3.05-3.15 (m, 1H), 3.68-3.74(m, 1H), 4.67 (d, J=10.80 Hz, 1H), 4.72-4.79 (m, 2H), 7.10-7.20 (m, 1H),7.45 (d, J=8.40 Hz, 1H), 7.91 (s, 1H), 8.22 (s, 1H). MS (ESI, pos. ion)m/z 433 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2-(oxetan-3-yl)ethoxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-47)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.05-1.15 (m, 7H), 1.21-1.37 (m, 1H),2.05-2.15 (m, 5H), 2.25-2.42 (m, 2H), 2.82-2.95 (m, 1H), 3.18-3.30 (m,1H), 3.55-3.78 (m, 3H), 4.46 (t, J=6.30 Hz, 2H), 4.65-4.83 (m, 2H),4.83-4.89 (m, 1H), 7.01-7.11 (m, 1H), 7.37 (d, J=8.40 Hz, 1H), 7.84 (s,1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 396 [M+H]⁺.

1-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((2,2-difluorocyclopropyl)methoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-48)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.01-1.15 (m, 8H), 1.21-1.35 (m, 1H),1.45-1.55 (m, 1H), 1.90-2.05 (m, 1H), 2.16 (s, 3H), 2.25-2.45 (m, 2H),2.95-3.05 (m, 1H), 3.58-3.75 (m, 2H), 3.85-3.99 (m, 1H), 4.67-4.82 (m,1H), 7.05-7.12 (m, 1H), 7.42 (d, J=8.40 Hz, 1H), 7.89 (s, 1H), 8.10 (s,1H). MS (ESI, pos. ion) m/z 402 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-49)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.19 (m, 7H), 1.15-1.42 (m, 1H), 2.17(s, 3H), 2.28-2.45 (m, 2H), 2.95-3.05 (m, 1H), 3.68-3.75 (m, 1H),3.79-3.95 (m, 4H), 4.45-4.57 (m, 4H), 4.68-4.82 (m, 1H), 7.05-7.12 (m,1H), 7.35 (d, J=8.40 Hz, 1H), 7.77 (s, 1H), 7.99 (s, 1H). MS (ESI, pos.ion) m/z 412 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((3-fluorooxetan-3-yl)methoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-50)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.99-1.15 (m, 7H), 1.25-1.41 (m, 1H), 2.16(s, 3H), 2.28-2.45 (m, 2H), 2.95-3.05 (m, 1H), 3.65-3.75 (m, 1H),3.99-4.25 (m, 2H), 4.55-4.85 (m, 5H), 7.05-7.15 (m, 1H), 7.41 (d, J=8.70Hz, 1H), 7.84 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 400 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3,3-difluorocyclobutoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-51)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.15 (m, 7H), 1.15-1.25 (m, 1H), 2.15(s, 3H), 2.20-2.48 (m, 2H), 2.55-2.89 (m, 4H), 2.91-3.01 (m, 1H),3.68-3.75 (m, 1H), 4.25-4.35 (m, 1H), 4.65-4.80 (m, 1H), 7.05-7.11 (m,1H), 7.38 (d, J=8.40 Hz, 1H), 7.82 (s, 1H), 8.05 (s, 1H). MS (ESI, pos.ion) m/z 402 [M+H]⁺.

(S)-1-(5-(azetidin-3-ylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-52)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.00-1.15 (m, 7H), 1.21-1.39 (m, 1H), 2.16(s, 3H), 2.25-2.45 (m, 2H), 2.75-3.10 (m, 3H), 3.48-3.65 (m, 2H),3.70-3.95 (m, 4H), 4.69-4.85 (m, 1H), 7.05-7.11 (m, 1H), 7.37 (d, J=8.40Hz, 1H), 7.82 (s, 1H), 8.03 (s, 1H). MS (ESI, pos. ion) m/z 381 [M+H]⁺.

(S)-(5-cyclobutoxy-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-53)

¹H NMR (300 MHz, CDCl₃) δ ppm 0.65-0.67 (m, 1H), 0.81-0.92 (m, 1H),0.93-1.03 (m, 1H), 1.13 (d, J=6.60 Hz, 3H), 1.23-1.32 (m, 1H), 1.33-1.42(m, 1H), 1.60-1.70 (m, 1H), 1.83-1.87 (m, 2H), 2.03-2.26 (m, 4H),2.27-2.44 (m, 2H), 2.91-3.07 (m, 1H), 4.05-4.28 (m, 4H), 4.68-4.82 (m,1H), 7.15-7.28 (m, 1H), 7.92-8.08 (m, 2H). MS (ESI, pos. ion) m/z 367[M+H]⁺.

(S)-(5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-54)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.55-0.65 (m, 1H), 0.72-0.89 (m, 2H), 1.13(d, J=6.60 Hz, 4H), 1.13-1.40 (m, 2H), 1.41-1.70 (m, 1H), 1.71-1.90 (m,1H), 1.90-1.93 (m, 4H), 2.14-2.39 (m, 2H), 2.90-3.02 (m, 1H), 3.99-4.16(m, 1H), 4.55-4.65 (m, 1H), 7.05 (d, J=8.10 Hz, 1H), 7.31 (d, J=8.10 Hz,1H), 7.88 (s, 1H). MS (ESI, pos. ion) m/z 352 [M+H]⁺.

(S)-(5-cyclobutoxy-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-55)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.65-0.79 (m, 1H), 0.85-1.01 (m, 2H), 1.13(d, J=6.60 Hz, 4H), 1.25-1.51 (m, 2H), 1.51-1.76 (m, 1H), 1.85-2.01 (m,1H), 2.01-2.57 (m, 6H), 2.99-3.15 (m, 1H), 3.85-3.04 (m, 3H), 4.12-4.31(m, 1H), 4.61-4.79 (m, 1H), 7.15 (d, J=8.10 Hz, 1H), 7.39 (d, J=8.10 Hz,1H), 7.86 (s, 1H), 7.99 (s, 1H). MS (ESI, pos. ion) m/z 367 [M+H]⁺.

(S)-(5-cyclobutoxy-2-methyl-6-(1H-pyrazol-5-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-56)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.61-0.85 (m, 1H), 0.85-1.03 (m, 2H), 1.15(d, J=6.60 Hz, 4H), 1.25-1.51 (m, 2H), 1.51-1.80 (m, 1H), 1.81-2.28 (m,5H), 2.29-2.60 (m, 2H), 2.99-3.20 (m, 1H), 4.06-4.29 (m, 1H), 4.68-4.82(m, 1H), 7.15 (br s, 1H), 7.04-7.32 (m, 1H), 7.61 (br s, 2H). MS (ESI,pos. ion) m/z 352 [M+H]⁺.

(S)-(5-cyclobutoxy-2-methyl-6-(1-methyl-1H-imidazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-57)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.63-0.78 (m, 1H), 0.87-0.98 (m, 2H), 1.29(d, J=13.20 Hz, 4H), 1.25-1.36 (m, 1H), 1.37-1.51 (m, 1H), 1.61-1.77 (m,1H), 1.84-1.96 (m, 1H), 2.05-2.49 (m, 6H), 2.99-3.13 (m, 1H), 3.81 (s,3H), 4.13-4.35 (m, 1H), 4.62-4.77 (m, 1H), 7.17 (d, J=8.40 Hz, 1H), 7.70(s, 1H), 7.64-7.76 (m, 2H). MS (ESI, pos. ion) m/z 366 [M+H]⁺.

(S)-methyl5-(1-(tert-butoxycarbonyl)azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-58)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.05-1.21 (m, 7H), 1.39-1.55 (m, 10H),2.18-2.28 (m, 1H), 2.40-2.53 (m, 1H), 2.85-2.95 (m, 1H), 3.68-3.75 (m,1H), 3.79 (s, 3H), 3.78-4.05 (m, 4H), 4.50-4.65 (m, 2H), 7.28-7.30 (m,2H), 7.80 (s, 1H), 8.03 (s, 1H). MS (ESI, pos. ion) m/z 483 [M+H]⁺.

(S)-methyl5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-59)

(S)-Methyl5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylatewas prepared by treating a solution of (S)-methyl5-(1-(tert-butoxycarbonyl)azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylatein dichloromethane with trifluoroacetic acid according to the procedureoutlined in Example 5-1, Step 3. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.15(m, 7H), 1.40-1.58 (m, 1H), 2.15-2.25 (m, 1H), 2.35-2.50 (m, 1H),2.80-2.92 (m, 1H), 3.40-3.59 (m, 2H), 3.60-3.81 (m, 6H), 4.43-4.62 (m,2H), 7.21-7.32 (m, 2H), 7.75 (s, 1H), 7.95 (s, 1H). MS (ESI, pos. ion)m/z 383 [M+H]⁺.

(S)-1-(5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-60)

(S)-1-(5-(Azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanonewas prepared from tert-butyl(S)-3-((1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)azetidine-1-carboxylateas outlined above for Examples 1-58 and 1-59. ¹H NMR (400 MHz, CD₃OD) δppm 0.85-1.05 (m, 7H), 1.10-1.25 (m, 1H), 2.04 (s, 3H), 2.05-2.35 (m,2H), 2.78-2.88 (m, 1H), 3.34-3.48 (m, 2H), 3.55-3.75 (m, 3H), 4.35-4.45(m, 1H), 4.55-4.65 (m, 1H), 6.85-7.05 (m, 1H), 7.25 (d, J=8.40 Hz, 1H),7.69 (s, 1H), 7.97 (s, 1H). MS (ESI, pos. ion) m/z 367 [M+H]⁺.

Methyl(S)-5-cyclobutoxy-6-(1-(1,1-dioxidothietan-3-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-61)

MS (ESI, pos. ion) m/z 446 [M+H]⁺.

Methyl(2S)-5-cyclobutoxy-6-(1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-62)

MS (ESI, pos. ion) m/z 474 [M+H]⁺.

(R)-2-((S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-2-fluoroacetamide(I-63)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.03-1.30 (m, 7H), 1.32-1.38 (m, 2H), 2.17(s, 3H), 2.35-2.42 (m, 2H), 3.08-3.17 (m, 1H), 3.65-3.72 (m, 1H),4.75-4.77 (m, 1H), 5.42-5.63 (m, 1H), 7.22-7.24 (m, 1H), 7.47-7.50 (m,1H), 7.86 (s, 1H), 8.15 (s, 1H). MS (ESI, pos. ion) m/z 387 [M+H]⁺.Stereochemistry arbitrarily assigned.

2-((S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-2-fluoroacetamide(I-64)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.00-1.21 (m, 7H), 1.21-1.40 (m, 2H), 2.17(s, 3H), 2.25-2.45 (m, 2H), 3.03-3.19 (m, 1H), 3.65-3.72 (m, 1H),4.68-4.84 (m, 1H), 5.53 (d, J=61.20 Hz, 1H), 7.15-7.25 (m, 1H), 7.49 (d,J=8.40 Hz, 1H), 7.86 (s, 1H), 8.11 (s, 1H). MS (ESI, pos. ion) m/z 387[M+H]⁺. Stereochemistry arbitrarily assigned.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((3-fluorooxetan-3-yl)methoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-65)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.05-1.23 (m, 7H), 1.41-1.71 (m, 1H),2.12-2.38 (m, 1H), 2.47-2.70 (m, 1H), 2.81-3.05 (m, 1H), 3.65-3.73 (m,1H), 3.78 (s, 3H), 3.96-4.19 (m, 2H), 4.55-4.83 (m, 5H), 7.28-7.41 (m,2H), 7.82 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 416 [M+H]⁺.

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)-2,2-difluoroacetamide(I-66)

¹H NMR (400 MHz, CDCl₃) δ ppm 0.93-1.19 (m, 8H), 2.06 (s, 3H), 2.16-2.22(m, 1H), 2.30-2.37 (m, 1H), 2.95-2.98 (m, 1H), 3.55-3.61 (m, 1H),4.61-4.77 (m, 1H), 7.18 (s, 1H), 7.41 (d, J=8.00 Hz, 1H), 7.74 (s, 1H),8.05 (s, 1H). MS (ESI, pos. ion) m/z 405 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-2-methylpropoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-67)

¹H NMR (300 MHz, CDCl₃) δ ppm 1.04-1.17 (m, 7H), 1.24-1.53 (m, 7H), 2.17(s, 3H), 2.21-2.35 (m, 2H), 2.96-3.01 (m, 1H), 3.57-3.64 (m, 3H),4.75-4.85 (m, 1H), 6.91-6.98 (m, 1H), 7.30-7.33 (m, 1H), 7.81 (s, 1H),7.99 (s, 1H). MS (ESI, pos. ion) m/z 386 [M+H]⁺.

(S)-methyl5-cyclobutoxy-2-methyl-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-68)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.17 (d, J=6.30 Hz, 3H), 1.25-1.50 (m,2H), 1.55-1.67 (m, 1H), 2.05-2.21 (m, 8H), 2.22-2.29 (m, 1H), 2.35-2.49(m, 1H), 2.91-3.01 (m, 1H), 3.52-3.66 (m, 2H), 3.77 (s, 3H), 4.05-4.21(m, 3H), 4.42-4.61 (m, 2H), 7.25-7.36 (m, 2H), 7.84 (s, 1H), 8.07 (s,1H). MS (ESI, pos. ion) m/z 426 [M+H]⁺.

(S)-(5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-69)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.62-0.71 (m, 1H), 0.85-1.03 (m, 3H),1.08-1.20 (m, 8H), 1.37-1.48 (m, 1H), 1.59-1.71 (m, 2H), 2.10-2.31 (m,5H), 2.41-2.51 (m, 1H), 3.07-3.13 (m, 1H), 3.69-3.78 (m, 1H), 4.10-4.22(m, 1H), 4.68-4.75 (m, 1H), 7.28 (d, J=10.80 Hz, 1H), 7.90 (s, 1H), 8.12(s, 1H). MS (ESI, pos. ion) m/z 410 [M+H]⁺.

(S)-(5-cyclobutoxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-70)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.55-0.89 (m, 4H), 0.99-1.18 (m, 4H),1.26-1.35 (m, 1H), 1.48-1.61 (m, 2H), 1.99-2.41 (m, 6H), 2.90-3.01 (m,1H), 4.09-4.13 (m, 1H), 4.55-4.65 (m, 1H), 7.43 (d, J=10.80 Hz, 1H),7.92-8.21 (m, 2H). MS (ESI, pos. ion) m/z 370 [M+H]⁺.

(S)-methyl5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-71)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.08-1.20 (m, 7H), 1.22-1.41 (m, 2H),1.60-1.71 (m, 1H), 2.05-2.20 (m, 4H), 2.25-2.42 (m, 2H), 2.96-3.05 (m,1H), 3.67-3.80 (m, 4H), 4.11-4.19 (m, 1H), 4.38-4.49 (m, 1H), 7.14 (d,J=11.20 Hz, 1H), 7.85 (s, 1H), 8.06 (s, 1H). MS (ESI, pos. ion) m/z 400[M+H]⁺.

(S)-methyl5-cyclobutoxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-72)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.17 (d, J=6.30 Hz, 3H), 1.25-1.35 (m,2H), 1.55-1.65 (m, 1H), 2.01-2.18 (m, 4H), 2.23-2.41 (m, 2H), 2.95-3.07(m, 1H), 3.74 (s, 3H), 4.07-4.15 (m, 1H), 4.39-4.45 (m, 1H), 7.15 (d,J=14.40 Hz, 1H), 8.00 (s, 2H). MS (ESI, pos. ion) m/z 360 [M+H]⁺.

(S)-1-(5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-73)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.10-1.18 (m, 8H), 1.35-1.45 (m, 1H),1.59-1.70 (m, 1H), 1.95-2.25 (m, 8H), 2.42-2.51 (m, 1H), 3.05-3.11 (m,1H), 3.70-3.78 (m, 1H), 4.15-4.20 (m, 1H), 4.70-4.80 (m, 1H), 7.29 (d,J=11.20 Hz, 1H), 7.90 (s, 1H), 8.12 (s, 1H). MS (ESI, pos. ion) m/z 384[M+H]⁺.

(S)-1-(5-cyclobutoxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-74)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.10-1.18 (m, 4H), 1.35-1.45 (m, 1H),1.59-1.70 (m, 1H), 2.05-2.25 (m, 8H), 2.42-2.51 (m, 1H), 3.05-3.11 (m,1H), 4.15-4.20 (m, 1H), 4.70-4.80 (m, 1H), 7.31 (d, J=11.20 Hz, 1H),8.05 (br s, 2H). MS (ESI, pos. ion) m/z 344 [M+H]⁺.

(S)-1-(5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-75)

(S)-1-(5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanonewas synthesized from(S)-1-(6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanoneaccording to the procedure described above in Step 2 of the synthesis of(S)-1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(Example 24). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.11-1.18 (m, 9H), 1.56-1.68(m, 1H), 1.98-2.47 (m, 9H), 2.94-3.08 (m, 1H), 3.70-3.81 (m, 1H),4.09-4.20 (m, 1H), 4.73-4.81 (m, 1H), 7.86 (s, 1H), 8.12 (s, 1H). MS(ESI, pos. ion) m/z 402 [M+H]⁺.

(S)-methyl5-(azetidin-3-ylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-76)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.21 (m, 6H), 1.48-1.68 (m, 1H),2.18-2.28 (m, 1H), 2.48-2.63 (m, 1H), 2.83-2.99 (m, 1H), 3.65-3.99 (m,9H), 4.55-4.68 (m, 1H), 7.25-7.35 (m, 2H), 7.81 (s, 1H), 8.01 (s, 1H).MS (ESI, pos. ion) m/z 397 [M+H]⁺.

Example 25(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone.(I-77)

Step 1.(S)-1-(6-bromo-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.025 g, 0.088 mmol), 2-chloroquinazoline (0.017 g, 0.106 mmol), andpotassium carbonate (0.024 g, 0.176 mmol) in N,N-dimethylformamide (1.0mL) was stirred in the microwave at 100° C. for 4 h. The reactionmixture was cooled to room temperature and water was added. The mixturewas extracted with dichloromethane and the combined organic phases werewashed with water and brine, dried over anhydrous sodium sulfate,filtered, and concentrated to afford a yellow oil. This material waspurified via column chromatography on silica gel (Biotage 10 g column,gradient elution with 50-100% ethyl acetate-hexane) to afford(S)-1-(6-bromo-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.023 g, 63%). MS (ESI, pos. ion) m/z 412, 414 [M+H]⁺.

Step 2.(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of(S)-1-(6-bromo-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.025 g, 0.061 mmol),1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.017 g, 0.073 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (XPhos 2nd generation precatalyst) (2.4 mg, 0.003 mmol),and cesium carbonate (0.059 g, 0.182 mmol) in 1,4-dioxane (2.0 mL) andwater (0.40 mL) was heated at 100° C. for 2 h. The reaction mixture wasfiltered through Celite and concentrated to afford an orange oil. Thismaterial was purified via column chromatography on silica gel (Biotage25 g column, gradient elution with 25-100% ethyl acetate-hexane) toafford(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.012 g, 45%) as a white solid. MS (ESI, pos. ion) m/z 440. ¹H NMR (300MHz, DMSO-d₆) δ ppm 0.81-0.91 (m, 5H), 1.07 (d, J=6.74 Hz, 3H), 1.47 (m,1H), 2.03 (br dd, J=13.34, 6.89 Hz, 1H), 2.18 (s, 3H), 2.44 (m, 1H),3.55-3.67 (m, 1H), 4.63 (m, 1H), 7.41 (br s, 1H), 7.51-7.70 (m, 3H),7.72 (s, 1H), 7.91 (ddd, J=8.50, 7.04, 1.47 Hz, 1H), 8.06 (s, 1H), 8.10(d, J=8.21 Hz, 1H), 9.54 (s, 1H). MS (ESI, pos. ion) m/z 440 [M+H]⁺.

The following examples were made according to the procedure describedabove for Example 25:

(S)-1-(5-(benzo[d]oxazol-2-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-78)

MS (ESI, pos. ion) m/z 429 [M+H]⁺.

(S)-1-(5-(benzo[d]oxazol-2-yloxy)-2-methyl-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-79)

MS (ESI, pos. ion) m/z 445 [M+H]⁺.

(S)-1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methyl-5-(pyrimidin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-80)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.04 (d, J=6.45 Hz, 3H), 1.42 (m, 1H),1.93-2.10 (m, 1H), 2.16 (s, 3H), 2.28 (m, 1H), 2.40 (br t, J=7.18 Hz,1H), 3.64 (q, J=5.47 Hz, 2H), 4.05 (t, J=5.72 Hz, 2H), 4.64 (m, 1H),4.83 (t, J=5.28 Hz, 1H), 7.21 (t, J=4.84 Hz, 1H), 7.38 (br s, 1H), 7.52(d, J=8.50 Hz, 1H), 7.70 (s, 1H), 7.94 (s, 1H), 8.60 (d, J=4.69 Hz, 2H).MS (ESI, pos. ion) m/z 394 [M+H]⁺.

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)nicotinamide(I-81)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.91-1.01 (m, 4H), 1.16 (d, J=6.40 Hz,3H), 1.35-1.55 (m, 1H), 2.05-2.35 (m, 4H), 2.37-2.55 (m, 1H), 2.70-2.85(m, 1H), 3.51-3.59 (m, 1H), 4.70-4.85 (m, 1H), 7.11-7.18 (m, 1H),7.20-7.35 (m, 1H), 7.53 (d, J=8.40 Hz, 1H), 7.32 (s, 1H), 7.96 (s, 1H),8.01-8.09 (m, 1H), 8.35-8.39 (m, 1H). MS (ESI, pos. ion) m/z 432 [M+H]⁺.

(S)-1-(5-(1H-pyrazolo[3,4-d]pyrimidin-6-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-82)

¹H NMR (400 MHz, CD3OD) δ ppm 0.90-1.01 (m, 4H), 1.18 (d, J=6.40 Hz,3H), 1.35-1.52 (m, 1H), 2.15-2.45 (m, 5H), 2.60-2.72 (m, 1H), 3.52-3.59(m, 1H), 4.73-4.85 (m, 1H), 7.25-7.35 (m, 1H), 7.57 (d, J=8.40 Hz, 1H),7.78 (s, 1H), 7.99 (s, 1H), 8.19 (s, 1H), 9.05 (s, 1H). MS (ESI, pos.ion) m/z 430 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(thiazol-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-83)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.98-1.05 (m, 4H), 1.15 (d, J=6.60 Hz,3H), 1.39-1.53 (m, 1H), 2.15-2.45 (m, 5H), 2.70-2.82 (m, 1H), 3.58-3.65(m, 1H), 4.70-4.85 (m, 1H), 6.95 (d, J=4.20 Hz, 1H), 7.18 (d, J=4.20 Hz,1H), 7.30-7.45 (m, 1H), 7.60 (d, J=8.40 Hz, 1H), 7.79 (s, 1H), 7.99 (s,1H). MS (ESI, pos. ion) m/z 395 [M+H]⁺.

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)nicotinonitrile(I-84)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.95-1.02 (m, 4H), 1.15 (d, J=6.60 Hz,3H), 1.35-1.52 (m, 1H), 2.15-2.38 (m, 5H), 2.51-2.63 (m, 1H), 3.53-3.63(m, 1H), 4.70-4.85 (m, 1H), 7.15-7.19 (m, 1H), 7.25-7.35 (m, 1H), 7.51(d, J=8.40 Hz, 1H), 7.70 (s, 1H), 7.92 (s, 1H), 8.15-8.25 (m, 2H). MS(ESI, pos. ion) m/z 414 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(4-(trifluoromethyl)pyrimidin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-85)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.95-1.05 (m, 4H), 1.16 (d, J=6.60 Hz,3H), 1.40-1.58 (m, 1H), 2.15-2.45 (m, 5H), 2.55-2.65 (m, 1H), 3.55-3.65(m, 1H), 4.70-4.85 (m, 1H), 7.25-7.35 (m, 1H), 7.53-7.60 (m, 2H), 7.76(s, 1H), 7.99 (s, 1H), 8.85 (d, J=5.10 Hz, 1H). MS (ESI, pos. ion) m/z458 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3-(trifluoromethyl)pyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-86)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.89-1.01 (m, 4H), 1.05-1.15 (m, 3H),1.20-1.45 (m, 1H), 1.95-2.25 (m, 5H), 2.75-2.89 (m, 1H), 3.49-3.60 (m,1H), 4.70-4.85 (m, 1H), 7.11-7.19 (m, 1H), 7.20-7.35 (m, 1H), 7.54 (d,J=8.40 Hz, 1H), 7.68 (s, 1H), 7.84 (s, 1H), 8.09-8.19 (m, 2H). MS (ESI,pos. ion) m/z 457 [M+H]⁺.

(S)-1-(5-(3-chloropyridin-2-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-87)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.95-1.05 (m, 4H), 1.16 (d, J=6.60 Hz,3H), 1.35-1.60 (m, 1H), 2.10-2.30 (m, 5H), 2.50-2.63 (m, 1H), 3.55-3.60(m, 1H), 4.70-4.89 (m, 1H), 6.95-7.09 (m, 1H), 7.25-7.35 (m, 1H), 7.54(d, J=8.40 Hz, 1H), 7.78 (s, 1H), 7.82-7.89 (m, 1H), 7.91-7.99 (m, 2H).MS (ESI, pos. ion) m/z 423 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyrazin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-88)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.95-1.01 (m, 4H), 1.14 (d, J=5.40 Hz,3H), 1.30-1.48 (m, 1H), 2.10-2.40 (m, 5H), 2.55-2.68 (m, 1H), 3.50-3.65(m, 1H), 4.68-4.85 (m, 1H), 7.20-7.35 (m, 1H), 7.52 (d, J=8.40 Hz, 1H),7.69 (s, 1H), 7.92 (s, 1H), 7.99-8.03 (m, 1H), 8.22 (d, J=2.70 Hz, 1H),8.50 (d, J=1.20 Hz, 1H). MS (ESI, pos. ion) m/z 390 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-89)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.95-1.05 (m, 4H), 1.16 (d, J=6.60 Hz,3H), 1.32-1.50 (m, 1H0, 2.10-2.32 (m, 5H), 2.55-2.72 (m, 1H), 3.55-3.65(m, 1H), 4.72-4.90 (m, 1H), 6.94 (d, J=8.10 Hz, 1H0, 7.02-7.10 (m, 1H),7.32 (br s, 1H), 7.58 (d, J=8.40 Hz, 1H), 7.74 (s, 1H), 7.75-7.85 (m,1H), 7.93 (s, 1H), 8.05-8.09 (m, 1H). MS (ESI, pos. ion) m/z 389 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(4,6-dimethylpyrimidin-2-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-90)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.95-1.01 (m, 4H), 1.14 (d, J=6.30 Hz,3H), 1.30-1.49 (m, 1H), 2.10-2.35 (m, 11H), 2.52-2.65 (m, 1H), 3.55-3.65(m, 1H), 4.70-4.85 (m, 1H), 6.93 (s, 1H), 7.20-7.35 (m, 1H), 7.54 (d,J=8.10 Hz, 1H), 7.75 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 418[M+H]⁺.

(S)-6-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)pyridazine-3-carbonitrile(I-91)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.95-1.01 (m, 4H), 1.15 (d, J=6.60 Hz,3H), 1.45 (br s, 1H), 2.15-2.32 (m, 5H), 2.55-2.72 (m, 1H), 3.52-3.69(m, 1H), 4.75-4.90 (m, 1H), 7.39 (br s, 1H), 7.54 (d, J=8.10 Hz, 1H),7.62-7.69 (m, 2H), 7.92 (s, 1H), 8.12 (d, J=9.30 Hz, 1H). MS (ESI, pos.ion) m/z 415 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(5-methylpyrimidin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-92)

¹H NMR (400 MHz, CDCl₃) δ ppm 0.90-0.92 (m, 4H), 1.04 (d, J=6.40 Hz,3H), 1.35 (m, 1H), 2.07-2.14 (m, 8H), 2.49-2.55 (m, 1H), 3.45-3.51 (m,1H), 4.68 (m, 1H), 7.19 (m, 1H), 7.44 (d, J=8.40 Hz, 1H), 7.64 (s, 1H),7.84 (s, 1H), 8.27 (d, J=4.80 Hz, 2H). MS (ESI, pos. ion) m/z 404[M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2-(trifluoromethyl)pyrimidin-4-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-93)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.02 (s, 4H), 1.15 (s, 3H), 1.49 (s, 1H),2.19-2.38 (m, 5H), 2.52-2.63 (m, 1H), 3.55-3.63 (m, 1H), 4.76-4.82 (m,1H), 7.29-7.49 (m, 2H), 7.56 (d, J=8.40 Hz, 1H), 7.70 (s, 1H), 7.94 (s,1H), 8.78 (s, 1H). MS (ESI, pos. ion) m/z 458 [M+H]⁺.

The following examples were made according to the procedure describedabove for Example 25, with the following changes: (1) In Step 2,tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatewas used instead of1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2) The Boc group was removed according to the procedure described belowin Step 3 of Example 27.

(S)-(5-(6-chloropyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-94)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.73-0.82 (m, 1H), 0.91-1.02 (m, 2H),1.12-1.21 (m, 4H), 1.45-1.53 (m, 1H), 1.85-2.00 (m, 2H), 2.00 (s, 3H),2.22-2.41 (m, 2H), 2.63-2.71 (m, 1H), 2.72-2.82 (m, 2H), 3.16-3.24 (m,2H), 4.22-4.31 (m, 1H), 4.71-4.85 (m, 1H), 6.87 (d, J=8.10 Hz, 1H), 7.07(d, J=7.50 Hz, 1H), 7.39 (d, J=8.40 Hz, 1H), 7.57 (d, J=8.40 Hz, 1H),7.73-7.77 (m, 2H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 492 [M+H]⁺.

(S)-cyclopropyl(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(pyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-95)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.73-0.82 (m, 1H), 0.89-1.01 (m, 2H),1.12-1.24 (m, 4H), 1.41-1.51 (m, 1H), 2.05-2.37 (m, 7H), 2.62-2.71 (m,1H), 3.14-3.22 (m, 2H), 3.50-3.64 (m, 2H), 4.45-4.55 (m, 1H), 4.78-4.85(m, 1H), 6.92 (d, J=8.40 Hz, 1H), 7.04-7.09 (m, 1H), 7.39 (d, J=8.40 Hz,1H), 7.59 (d, J=8.40 Hz, 1H), 7.77-7.81 (m, 2H), 7.96 (s, 1H), 8.05 (t,J=3.60 Hz, 1H). MS (ESI, pos. ion) m/z 458 [M+H]⁺.

(S)-methyl2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(pyridin-2-yloxy)-3,4-dihydroquinoline-1(2H)-carboxylate(I-96)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.16 (d, J=6.90 Hz, 3H), 1.25-1.33 (m,1H), 1.54-1.64 (m, 1H), 1.73-1.90 (m, 2H), 1.95-2.15 (m, 3H), 2.40-2.50(m, 1H), 2.53-2.76 (m, 3H), 3.09-3.16 (m, 2H), 3.81 (s, 3H), 4.15-4.24(m, 1H), 4.60-4.71 (m, 1H), 6.83 (d, J=8.40 Hz, 1H), 7.01-7.09 (m, 1H),7.47-7.61 (m, 2H), 7.70-7.80 (m, 2H), 7.89 (s, 1H), 8.06 (m, 1H). MS(ESI, pos. ion) m/z 448 [M+H]⁺.

(S)-cyclopropyl(5-(6-fluoropyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-97)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.67-0.74 (m, 1H), 0.81-0.92 (m, 2H),1.02-1.08 (m, 4H), 1.42-1.49 (m, 1H), 1.62-1.71 (m, 2H), 1.82-1.95 (m,3H), 2.05-2.16 (m, 1H), 2.05-2.16 (m, 1H), 2.27-2.34 (m, 1H), 2.46-2.58(m, 3H), 2.95-3.05 (m, 2H), 4.05-4.16 (m, 1H), 4.66-4.74 (m, 1H),6.78-6.81 (m, 1H), 6.95-7.00 (m, 1H), 7.33-7.37 (m, 1H), 7.66 (s, 1H),7.96-8.05 (m, 2H). MS (ESI, pos. ion) m/z 476 [M+H]⁺.

Example 26(S)-cyclopropyl(5-(6-methoxypyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-98)

A mixture of(S)-cyclopropyl(5-(6-fluoropyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.024 g, 0.05 mmol), and sodium methoxide (0.015 g, 0.28 mmol) inN,N-dimethylformamide (1 mL) stirred overnight at 80° C. The reactionmixture was cooled to room temperature, diluted with ethyl acetate (15mL), washed with brine (2×5 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified bypreparative-HPLC with the following conditions (Waters I): Column,SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammoniumbicarbonate) and acetonitrile (16% to 34% acetonitrile in 10 min, flowrate: 20 mL/min); Detector, UV 220&254 nm. This afforded(S)-cyclopropyl(5-(6-methoxypyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.0033 g, 13%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm0.79-0.87 (m, 1H), 0.91-1.00 (m, 2H), 1.10-1.18 (m, 4H), 1.39-1.49 (m,1H), 1.79-1.84 (m, 2H), 1.97-2.09 (m, 3H), 2.18-2.41 (m, 2H), 2.62-2.79(m, 3H), 3.12-3.19 (m, 2H), 3.62 (s, 3H), 4.15-4.27 (m, 1H), 4.72-4.89(m, 1H), 6.41 (t, J=8.00 Hz, 2H), 7.36 (d, J=8.40 Hz, 1H), 7.55-7.65 (m,2H), 7.79 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 488 [M+H]⁺.

Example 27(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline(I-99)

Step 1.(2S)-6-bromo-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline

A 250-mL round-bottom flask was charged with(2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol(2.00 g, 6.45 mmol), bromocyclobutane (1.81 mL, 2.60 g, 19.3 mmol),cesium carbonate (6.3 g, 19.34 mmol) and acetonitrile (100 mL). Theresulting mixture was stirred for 6 h at 80° C. The reaction mixture wasfiltered through a pad of Celite and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (gradientelution with 0-10% ethyl acetate-petroleum ether) to afford(2S)-6-bromo-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline(2.00 g, 85%) as a colorless oil. MS (ES, m/z): 364,366 [M+H]⁺

Step 2. (S)-tert-butyl4-(4-(5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A 250-mL round-bottom flask was purged and maintained with an inertatmosphere of nitrogen, and charged with(2S)-6-bromo-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline(2.0 g, 5.5 mmol), tert-butyl4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(2.5 g, 6.63 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.45 g, 0.55 mmol), potassium carbonate (2.3 g,16.64 mmol), 1,4-dioxane (50 mL) and water (5 mL). The resulting mixturestirred overnight at 100° C. The reaction mixture was cooled to roomtemperature and then filtered through a pad of Celite. The filtrate wasconcentrated, and the residue was purified via column chromatography onsilica gel (gradient elution with 0-30% ethyl acetate-petroleum ether)to afford (S)-tert-butyl4-(4-(5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(2.2 g, 75%) as a light yellow solid. MS (ES, m/z): 535 [M+H]⁺

Step 3.(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline

Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a 0° C. solutionof (S)-tert-butyl4-(4-(5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.032 g, 0.060 mmol) in dichloromethane (2.0 mL). The ice bath wasremoved, and the mixture stirred at rt for 1.5 h. The reaction mixturewas concentrated, and the residue was partitioned betweendichloromethane and saturated aqueous sodium bicarbonate solution. Thelayers were separated and the organic phase was washed with brine, driedover anhydrous sodium sulfate, filtered, and concentrated to afford(S)-(5-cyclobutoxy-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.022 g, 85%) as an off-white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δppm 0.57-0.71 (m, 1H), 0.78-0.91 (m, 1H), 0.92-1.04 (m, 1H), 1.13 (d,J=6.45 Hz, 3H), 1.19-1.45 (m, 3H), 1.53-1.71 (m, 2H), 1.79-2.42 (m,11H), 2.74-2.92 (m, 2H), 2.94-3.09 (m, 1H), 3.30 (br d, J=12.61 Hz, 2H),4.04-4.21 (m, 1H), 4.28 (ddt, J=11.43, 7.62, 3.96, 3.96 Hz, 1H),4.66-4.84 (m, 1H), 7.12 (d, J=8.21 Hz, 1H), 7.28 (d, J=8.21 Hz, 1H),7.81 (s, 1H), 7.88 (s, 1H). MS (ESI, pos. ion) m/z 435 [M+H]⁺.

The following examples were made according to the procedure outlined forExample 27:

(S)-cyclopropyl(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(I-100)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.65-0.778 (m, 1H), 0.85-0.99 (m, 2H),1.01-1.19 (m, 7H), 1.25-1.42 (m, 1H), 1.70-1.82 (m, 2H), 1.85-2.05 (m,3H), 2.10-2.21 (m, 2H), 2.30-2.49 (m, 2H), 2.75-2.89 (m, 2H), 2.95-3.07(m, 1H), 3.17-3.20 (m, 2H), 3.58-3.72 (m, 2H), 4.28-4.42 (m, 1H),4.70-4.83 (m, 1H), 7.19 (d, J=8.10 Hz, 1H), 7.44 (d, J=8.10 Hz, 1H),7.93 (s, 1H), 8.12 (s, 1H). MS (ESI, pos. ion) m/z 423 [M+H]⁺

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-101)

¹H NMR (300 MHz, CD₃OD) 0.65-0.75 (m, 1H), 0.85-0.95 (m, 2H), 1.05-1.15(m, 4H), 1.20-1.40 (m, 2H), 1.50-1.70 (m, 1H), 1.80-1.95 (m, 1H),2.01-2.45 (m, 6H), 2.95-3.05 (m, 1H), 3.92-4.01 (m, 2H), 4.10-4.25 (m,3H), 4.65-4.75 (m, 1H), 5.25-5.40 (m, 1H), 7.15 (d, J=8.10 Hz, 1H), 7.40(d, J=8.70 Hz, 1H), 7.96 (s, 1H), 8.14 (s, 1H). MS (ESI, pos. ion) m/z407 [M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-102)

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-102)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.60-0.75 (m, 1H), 0.85-0.95 (m, 2H),1.00-1.08 (m, 3H), 1.10-1.18 (m, 4H), 1.25-1.38 (m, 1H), 1.70-1.80 (m,2H), 1.85-1.95 (m, 1H), 2.30-2.45 (m, 2H), 2.90-3.05 (m, 1H), 3.55-2.75(m, 2H), 3.95-4.05 (m, 2H), 4.15-4.25 (m, 2H), 4.65-4.75 (m, 1H),5.28-5.38 (m, 1H), 7.17 (d, J=8.40 Hz, 1H), 7.43 (d, J=8.40 Hz, 1H),8.00 (s, 1H), 8.15 (s, 1H). MS (ESI, pos. ion) m/z 395 [M+H]⁺.

(S)-(5-cyclobutoxy-8-fluoro-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-103)

¹H NMR (400 MHz, DMSO-d6) δ ppm 0.56-0.90 (m, 4H), 0.99-1.17 (m, 4H),1.25-1.34 (m, 1H), 1.47-1.59 (m, 2H), 1.74-1.81 (m, 2H), 1.95-2.28 (m,7H), 2.31-2.41 (m, 1H), 2.55-2.61 (m, 2H), 2.85-2.93 (m, 1H), 3.02-3.09(m, 2H), 4.05-4.24 (m, 2H), 4.56-4.67 (m, 1H), 7.42 (d, J=10.0 Hz, 1H),7.90 (s, 1H), 8.18 (s, 1H). MS (ESI, pos. ion) m/z 453 [M+H]+.

Example 28(S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-104)

Step 1.(S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.150 g, 0.528 mmol), 1-bromopropane (0.240 mL, 2.64 mmol), andpotassium tert-butoxide (0.296 g, 2.64 mmol) in DMF (3.0 mL) was heatedat 80° C. After 24 h, additional 1-bromopropane (0.240 mL, 2.64 mmol)was added and mixture stirred at 70° C. for 16 h. The reaction wasincomplete, so 1-bromopropane (0.240 mL, 2.64 mmol) and potassiumtert-butoxide (0.296 g, 2.64 mmol) were added, and the mixture wasstirred at 100° C. After 24 h, the reaction mixture was cooled to rt andwater was added. The mixture was extracted with dichloromethane and thecombined organic phases were washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated to afford a yellowoil. This material was purified via column chromatography on silica gel(Biotage 25 g column, gradient elution with 50-100% ethylacetate-hexane) to afford(S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.100 g, 58%) as a colorless oil. MS (ESI, pos. ion) m/z 326, 328[M+H]⁺

Step 2. (S)-tert-butyl4-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of(S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.050 g, 0.153 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.058 g, 0.153 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (XPhos 2nd generation precatalyst) (0.012 g, 0.015 mmol),and cesium carbonate (0.150 g, 0.460 mmol) in 1,4-dioxane (2.0 mL) andwater (0.40 mL) was heated in the microwave at 100° C. for 2.5 h. Thereaction mixture was filtered through Celite and concentrated to affordan orange oil. This material was purified via column chromatography onsilica gel (Biotage 25 g column, gradient elution with 50-100% ethylacetate-hexane) to afford (S)-tert-butyl4-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.063 g, 83%) as an off-white solid. MS (ESI, pos. ion) m/z 497 [M+H]⁺

Step 3.(S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone

Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of(S)-tert-butyl4-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.063 g, 0.127 mmol) in dichloromethane (2.0 mL) and the reactionmixture stirred at rt for 1.5 h. The reaction mixture was concentratedand the residue was partitioned between dichloromethane and saturatedaqueous sodium bicarbonate solution. The organic phase was separated,dried over anhydrous sodium sulfate, filtered, and concentrated toafford(S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.045 g, 89%) as a tan solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.91-1.12(m, 6H), 1.18-1.37 (m, 1H), 1.57-1.88 (m, 5H), 1.97 (br d, J=10.26 Hz,2H), 2.07 (s, 3H), 2.16-2.40 (m, 2H), 2.53-2.66 (m, 2H), 2.73-2.89 (m,1H), 3.03 (br d, J=12.61 Hz, 2H), 3.46-3.65 (m, 2H), 4.09-4.30 (m, 1H),4.62 (br d, J=5.86 Hz, 1H), 7.11 (br d, J=8.21 Hz, 1H), 7.38 (d, J=8.21Hz, 1H), 7.84 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion) m/z 397 [M+H]⁺.

The following examples were made according to the procedure outlined forExample 28:

(S)-1-(5-cyclobutoxy-8-fluoro-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-105)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.93-1.17 (m, 4H), 1.27-1.41 (m, 1H),1.55-1.68 (m, 1H), 1.92-2.48 (m, 13H), 2.70-2.83 (m, 2H), 3.02-3.10 (m,1H), 3.10-3.22 (m, 2H), 4.05-4.18 (m, 1H), 4.25-4.43 (m, 1H), 4.70-4.88(m, 1H), 7.15-7.35 (m, 1H), 7.90 (s, 1H), 8.13 (s, 1H). MS (ESI, pos.ion) m/z 427 [M+H]⁺.

(S)-1-(5-cyclobutoxy-7,8-difluoro-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-106)

(S)-1-(5-cyclobutoxy-7,8-difluoro-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanonewas synthesized from(S)-1-(6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanoneaccording to the procedures described above in Steps 2 and 3 of thesynthesis of(S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(Example 4-1). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.12-1.28 (m, 4H),1.30-1.41 (m, 1H), 1.56-1.68 (m, 1H), 1.98-2.20 (m, 11H), 2.32-2.49 (m,2H), 2.75-2.88 (m, 2H), 2.99-3.10 (m, 1H), 3.21-3.25 (m, 2H), 4.17-4.20(m, 1H), 4.35-4.45 (m, 1H), 4.75-4.82 (m, 1H), 7.91 (s, 1H), 8.12 (s,1H). MS (ESI, pos. ion) m/z 445 [M+H]⁺.

Example 29 (S)-methyl2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate(I-107)

Step 1. (S)-methyl6-bromo-2-methyl-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of (S)-methyl6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.110g, 0.366 mmol), 1-bromopropane (0.166 mL, 1.832 mmol), and potassiumtert-butoxide (0.103 g, 0.916 mmol) in DMF (3.0 mL) was heated in asealed tube at 100° C. After 24 h, additional 1-bromopropane (0.166 mL,1.832 mmol) and potassium tert-butoxide (0.103 g, 0.916 mmol) were addedand the mixture was heated in a sealed tube at 100° C. for 24 h. Thereaction mixture was cooled to rt and water was added. The mixture wasextracted with dichloromethane and the combined organic phases werewashed with water and brine, dried over anhydrous sodium sulfate,filtered, and concentrated to afford a yellow oil. This material waspurified via column chromatography on silica gel (Biotage 25 g column,gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-methyl6-bromo-2-methyl-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate (0.120g, 96%) as a colorless oil. MS (ESI, pos. ion) m/z 342, 344 [M+H]⁺.

Step 2. (S)-methyl6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of (S)-methyl6-bromo-2-methyl-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate (0.060g, 0.175 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.066 g, 0.175 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (XPhos 2nd generation precatalyst) (0.014 g, 0.018 mmol),and cesium carbonate (0.171 g, 0.526 mmol) in 1,4-dioxane (2.0 mL) andwater (0.40 mL) was heated in the microwave at 100° C. for 5 h. Thereaction mixture was filtered through Celite and concentrated to affordan orange oil. This material was purified via column chromatography onsilica gel (Biotage 25 g column, gradient elution with 0-50% ethylacetate-hexane) to afford (S)-methyl6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate(0.090 g, 100%) as a colorless oil. MS (ESI, pos. ion) m/z 513 [M+H]⁺.

Step 3. (S)-methyl2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate

Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of(S)-methyl6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate(0.090 g, 0.176 mmol) in dichloromethane (2.0 mL) and the reactionmixture stirred at rt for 1 h. The reaction mixture was concentrated andthe residue was partitioned between dichloromethane and saturatedaqueous sodium bicarbonate solution. The organic phase was separated,dried over anhydrous sodium sulfate, filtered, and concentrated toafford (S)-methyl2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate(0.070 g, 97%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.97 (t, J=7.48 Hz, 3H), 1.05-1.13 (m, 3H), 1.48 (dq, J=13.05, 6.50 Hz,1H), 1.63-1.87 (m, 5H), 1.88-2.03 (m, 2H), 2.05-2.19 (m, 2H), 2.53-2.66(m, 2H), 2.72-2.90 (m, 1H), 3.04 (br d, J=12.61 Hz, 2H), 3.54 (br t,J=6.60 Hz, 2H), 3.67 (s, 3H), 4.11-4.32 (m, 1H), 4.37-4.57 (m, 1H),7.21-7.31 (m, 1H), 7.31-7.40 (m, 1H), 7.81 (s, 1H), 8.06 (s, 1H). MS(ESI, pos. ion) m/z 413 [M+H]⁺. MS (ESI, pos. ion) m/z 413 [M+H]⁺.

Example 30 (2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-108)

Step 1. Methyl(S)-6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A 100-mL round-bottom was charged with methyl(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(600 mg, 2.00 mmol), bromocyclobutane (807 mg, 5.98 mmol), acetonitrile(30 mL), and cesium carbonate (1.96 g, 6.00 mmol). The mixture stirredfor 6 h at 80° C. in an oil bath. After cooling to room temperature, thereaction mixture was poured into 10 mL of water and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (3×15 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (eluting with 8:1, ethylacetate/petroleum ether) to afford methyl(S)-6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.67 g, 95%) as colorless oil. MS (ESI, pos. ion) m/z 354, 356[M+H]⁺.

Step 2. (2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

(2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from(S)-6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateand tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylateaccording to the procedures outlined above in Steps 2 and 3 for Example29. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (d, J=6.40 Hz, 3H), 1.25-1.65 (m,3H), 1.98-2.30 (m, 6H), 2.31-2.45 (m, 2H), 2.85-3.08 (m, 2H), 3.20-3.35(m, 3H), 3.79 (s, 3H), 4.10-4.15 (m, 1H), 4.49-4.55 (m, 1H), 4.90-5.05(m, 1H), 7.20-7.32 (m, 2H), 7.86 (s, 1H), 8.05 (s, 1H). MS (ESI, pos.ion) m/z 411 [M+H]⁺.

The following examples were made according to the procedure outlined forExample 30:

(2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-109)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.17 (d, J=6.30 Hz, 3H), 1.20-1.52 (m,2H), 1.55-1.75 (m, 1H), 1.95-2.30 (m, 7H), 2.35-2.50 (m, 3H), 2.85-3.00(m, 1H), 3.05-3.20 (m, 4H), 3.50-3.62 (m, 2H), 3.77 (s, 1H), 4.05-4.15(m, 1H), 4.45-4.55 (m, 1H), 4.85-5.00 (m, 1H), 7.20-7.30 (m, 2H), 7.85(s, 1H), 8.01 (s, 1H). MS (ESI, pos. ion) m/z 451 [M+H]⁺.

(S)-methyl5-cyclobutoxy-8-fluoro-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-110)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.14 (d, J=6.60 Hz, 3H), 1.21-1.38 (m,2H), 1.55-1.61 (m, 1H), 1.90-2.16 (m, 8H), 2.35-2.40 (m, 2H), 2.71-2.79(m, 2H), 2.95-3.15 (m, 1H), 3.15-3.22 (m, 2H), 3.71 (s, 3H), 4.05-4.16(m, 1H), 4.25-4.43 (m, 2H), 7.11 (d, J=11.40 Hz, 1H), 7.83 (s, 1H), 8.05(s, 1H). MS (ESI, pos. ion) m/z 443 [M+H]⁺.

Example 31rac-1-(2-methyl-6-(4-(methylsulfonyl)phenyl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-111)

Step 1.rac-1-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of rac-6-bromo-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline(0.022 g, 0.069 mmol) in dichloromethane (1 mL), and pyridine (0.017 mL,0.207 mmol) was cooled to 0° C. and treated with acetyl chloride (5.41μL, 0.076 mmol). The reaction mixture was then stirred at rt. After 10min, additional acetyl chloride (3.93 μL, 0.055 mmol) was added andstirring was continued at rt. After 75 min, the reaction mixture wasdiluted with dichloromethane and washed with 1 N aqueous hydrochloricacid solution (2×0.5 mL) and 5% aqueous sodium chloride solution (0.5mL). The dichloromethane layer was concentrated to afford cruderac-1-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.024 g, 96%) as a nearly colorless gum that solidified upon standing.The crude product was used without further purification. MS (ESI, pos.ion) m/z 360, 362 [M+H]⁺.

Step 2.rac-1-(2-methyl-6-(4-(methylsulfonyl)phenyl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone

A screw-cap vial equipped with a magnetic stir bar was charged withrac-1-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.024 g, 0.067 mmol), 4-(methylsulfonyl)phenylboronic acid (0.020 g,0.100 mmol), 1,4-dioxane (0.67 mL), 1.0 M aqueous sodium bicarbonate(0.200 mL, 0.200 mmol), and bis(triphenylphosphine)palladium(II)chloride (4.7 mg, 6.7 mol). The vial was flushed with nitrogen and thencapped. The reaction mixture was then heated to 80° C. for 3 h and thencooled to room temperature. The reaction mixture was diluted with 5%aqueous sodium chloride solution (0.5 mL) and ethyl acetate. The layerswere separated, and the aqueous layer was extracted with ethyl acetate.The combined extracts were concentrated under reduced pressure to afforda dark brown residue, which was then purified by preparative thin layerchromatography (1×1000 micron plate; eluting with 3:2 ethylacetate-hexanes). The major band was isolated (26 mg) and furtherpurified by preparative HPLC to affordrac-1-(2-methyl-6-(4-(methylsulfonyl)phenyl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone.¹H NMR (400 MHz, CDCl₃) δ ppm 1.17 (d, J=6.60 Hz, 3H), 1.45 (br s, 1H),2.07-2.24 (m, 1H), 2.27 (s, 3H), 2.29-2.37 (m, 1H), 2.71 (dt, J=16.13,6.42 Hz, 1H), 3.01 (s, 3H), 4.79 (br s, 1H), 6.59-6.69 (m, 2H),6.82-6.95 (m, 1H), 7.15 (t, J=7.70 Hz, 2H), 7.32 (br d, J=7.33 Hz, 2H),7.65 (d, J=8.43 Hz, 2H), 7.84 (d, J=8.43 Hz, 2H). MS (ESI, pos. ion) m/z436 [M+H]⁺.

Example 32rac-1-(2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (I-112)

A glass, screw-cap vial equipped with a magnetic stir bar was chargedwith a solution of rac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline(0.050 g, 0.21 mmol) in dichloromethane (1 mL) and pyridine (0.051 mL,0.630 mmol). The solution was cooled to 0° C. and acetyl chloride (0.015mL, 0.210 mmol) was added. The ice bath was removed and the reactionmixture stirred at rt. After 10 min, the reaction mixture was dilutedwith dichloromethane and washed with 1 N aqueous hydrochloric acidsolution (2×1 mL) followed by 5% aqueous sodium chloride solution (1mL). The organic layer was concentrated to a yellow oil, whichcrystallized upon standing. The crude product was purified bypreparative thin layer chromatography (1×1000 micron plate, eluting with2:1 hexanes-ethyl acetate) to yield1-(2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.0189 g,32%) as a nearly colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.13 (d,J=6.60 Hz, 3H), 1.36-1.55 (m, 1H), 2.11-2.27 (m, 4H), 2.36 (br s, 1H),2.85 (dt, J=16.04, 6.09 Hz, 1H), 4.88 (br s, 1H), 6.76 (d, J=8.80 Hz,1H), 6.89-6.96 (m, 2H), 6.96-7.04 (m, 1H), 7.04-7.11 (m, 1H), 7.12-7.19(m, 1H), 7.29-7.37 (m, 2H). MS (ESI, pos. ion) m/z 282 [M+H]⁺.

Example 33(S)-1-(5-cyclopropoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-113)

Step 1.(S)-1-(6-bromo-5-cyclopropoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A solution of(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(17.05 mg, 0.06 mmol) in DMF (500 μL) was added to a microwave reactionvial equipped with a magnetic stir bar. Bromocyclopropane (150 μL, 1.87mmol), sodium iodide (8.99 mg, 0.060 mmol) and cesium carbonate (98 mg,0.300 mmol) were then added and the reaction was sealed. The reactionwas heated in the microwave at 180° C. for 6 h. The mixture was dilutedwith ethyl acetate and washed with brine. The organic layer was driedover anhydrous sodium sulfate, filtered, and concentrated to afford(S)-1-(6-bromo-5-cyclopropoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.019 g, 100%) which was used without furtherpurification. MS (ESI, pos. ion) m/z 324, 326 [M+H]⁺.

Step 2.(S)-1-(5-cyclopropoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 1.5 mL reaction vial was charged with(S)-1-(6-bromo-5-cyclopropoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.019 g, 0.06 mmol) and 1,4-dioxane (50 μL).1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.2 M solution in 1,4-dioxane, 540 μL, 0.108 mmol) and potassiumcarbonate (1 M solution in water, 180 μL, 0.18 mmol) were added, and thereaction mixture was purged with nitrogen.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.02 M solution in 1,2-dichloroethane, 300 μL,0.006 mmol) was added, and the reaction was purged with nitrogen andheated to 80° C. on a heater shaker overnight. The reaction was dilutedwith ethyl acetate and washed with 1 N aqueous sodium hydroxidesolution. The aqueous layer was separated and washed with ethyl acetate,and the combined organic layers were concentrated under a stream ofnitrogen. The crude product was purified by mass triggered preparatoryHPLC. The product-containing fractions were combined and concentrated ina Genevac to afford(S)-1-(5-cyclopropoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.0039 g, 19%). MS (ESI, pos. ion) m/z 352 [M+H]⁺.

Example 34(S)-1-(2-methyl-6-(5-(methylsulfonyl)pyridin-2-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-114)

Step 1.(S)-1-(2-methyl-5-propoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of(S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.127 g, 0.389 mmol), bis(pinacolato)diboron (0.109 g, 0.428 mmol),potassium acetate (0.096 g, 0.973 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.028 g, 0.039 mmol) in 1,4-dioxane (3.0 mL) washeated at 80° C. After 24 h, additional portions of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.028 g, 0.039 mmol), bis(pinacolato)diboron(0.109 g, 0.428 mmol), and potassium acetate (0.096 g, 0.973 mmol) wereadded and the mixture was heated at 100° C. for 4 h. The reactionmixture was cooled to rt and filtered through Celite to afford a darkbrown oil. This material was purified via column chromatography onsilica gel (Biotage 25 g column, gradient elution with 25-50% ethylacetate-hexane) to afford(S)-1-(2-methyl-5-propoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.110 g, 76%) as a colorless oil. MS (ESI, pos. ion) m/z 374 [M+H]⁺.

Step 2.(S)-1-(2-methyl-6-(5-(methylsulfonyl)pyridin-2-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone

A mixture of(S)-1-(2-methyl-5-propoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.055 g, 0.147 mmol), 2-bromo-5-(methylsulfonyl)pyridine (0.037 g,0.155 mmol), XPhos Precatalyst 2nd Generation (0.012 g, 0.015 mmol), andcesium carbonate (0.144 g, 0.442 mmol) in 1,4-dioxane (2.0 mL) and water(0.40 mL) was heated in the microwave at 100° C. for 1.5 h. The reactionmixture was filtered through Celite and concentrated to afford an orangeoil. This material was purified via column chromatography on silica gel(Biotage 25 g column, gradient elution with 25-100% ethylacetate-hexane) to afford(S)-1-(2-methyl-6-(5-(methylsulfonyl)pyridin-2-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.016 g, 27%) as a tan solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.85 (t,J=7.33 Hz, 3H), 1.07 (d, J=6.45 Hz, 3H), 1.32-1.50 (m, 2H), 1.56 (dt,J=14.07, 7.04 Hz, 2H), 2.14 (s, 3H), 2.19-2.33 (m, 1H), 2.79-2.94 (m,1H), 3.37 (s, 3H), 3.50 (td, J=6.30, 2.64 Hz, 2H), 4.51-4.75 (m, 1H),7.33 (br d, J=8.50 Hz, 1H), 7.64 (d, J=8.50 Hz, 1H), 8.08-8.21 (m, 1H),8.36 (dd, J=8.50, 2.35 Hz, 1H), 9.14 (d, J=2.05 Hz, 1H). MS (ESI, pos.ion) m/z 403 [M+H]⁺.

Example 35(S)—N-(6-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)methanesulfonamide(I-115)

Step 1. N-(6-iodopyridin-3-yl)methanesulfonamide

N,N-Diisopropylethylamine (0.992 mL, 5.68 mmol) was added to a solutionof 6-iodopyridin-3-amine (0.500 g, 2.273 mmol) and methanesulfonylchloride (0.186 mL, 2.386 mmol) in 1,2-dichloroethane (10.0 mL), and themixture stirred at 50° C. for 2.5 h. The reaction mixture wasconcentrated to afford a brown oil which was dissolved in 1,4-dioxane(5.0 mL) and water (1.0 mL). Potassium hydroxide (0.128 g, 2.273 mmol)was added and the mixture stirred at 80° C. for 4 h. The reactionmixture was cooled to room temperature and then partitioned betweendichloromethane and water. The aqueous phase was separated and extractedwith dichloromethane. The combined organic phases were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated toafford a brown oil. This material was purified via column chromatographyon silica gel (Biotage 25 g column, gradient elution with 0-50% ethylacetate-hexane) to afford N-(6-iodopyridin-3-yl)methanesulfonamide(0.537 g, 79%) as a tan solid. MS (ESI, pos. ion) m/z 299 [M+H]⁺.

Step 2.(S)—N-(6-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)methanesulfonamide

A mixture of(S)-1-(2-methyl-5-propoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.055 g, 0.147 mmol), N-(6-iodopyridin-3-yl)methanesulfonamide (0.046g, 0.155 mmol), XPhos Precatalyst 2nd Generation (0.012 g, 0.015 mmol),and cesium carbonate (0.144 g, 0.442 mmol) in 1,4-dioxane (2.0 mL) andwater (0.40 mL) was heated in the microwave at 100° C. for 1.5 h. Thereaction mixture was filtered through Celite and concentrated to affordan orange oil. This material was purified via column chromatography onsilica gel (Biotage 25 g column, gradient elution with 25-100% ethylacetate-hexane) to afford(S)—N-(6-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)methanesulfonamide(0.007 g, 11%) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm0.79-0.85 (m, 3H), 1.08 (d, J=6.45 Hz, 3H), 1.17-1.55 (m, 3H), 2.12 (s,3H), 2.20-2.41 (m, 2H), 2.82-3.01 (m, 1H), 3.04 (s, 3H), 3.28-3.59 (m,2H), 4.76 (br s, 1H), 6.64-6.86 (m, 1H), 6.98 (br s, 1H), 7.52 (d,J=8.21 Hz, 1H), 7.68 (dd, J=8.79, 2.64 Hz, 1H), 7.87 (d, J=8.50 Hz, 1H),8.47 (d, J=2.64 Hz, 1H). MS (ESI, pos. ion) m/z 418 [M+H]⁺.

The following examples were made according to the procedure outlined forExample 34:

(S)-2-(1-acetyl-2-methyl-6-(5-(methylsulfonyl)pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)-N,N-dimethylacetamide(I-116)

¹H NMR (300 MHz, CDCl₃) δ ppm 1.09 (d, J=6.74 Hz, 3H), 2.07-2.20 (m,3H), 2.20-2.42 (m, 2H), 2.73 (s, 3H), 2.83-2.94 (m, 3H), 2.94-3.07 (m,1H), 3.11 (s, 3H), 4.03 (dt, J=19.35, 6.89 Hz, 1H), 4.20-4.30 (m, 2H),4.61-4.82 (m, 1H), 7.00-7.17 (m, 1H), 7.63 (d, J=8.50 Hz, 1H), 8.15-8.20(m, 2H), 9.06-9.22 (m, 1H). MS (ESI, pos. ion) m/z 446 [M+H]⁺.

(S)-1-(6-(benzo[d]oxazol-2-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-117)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.01 (t, J=7.48 Hz, 3H), 1.08 (d, J=6.45Hz, 3H), 1.38-1.58 (m, 2H), 1.79 (dq, J=14.14, 7.01 Hz, 2H), 2.17 (s,3H), 2.20-2.32 (m, 1H), 2.77-3.01 (m, 1H), 3.84 (t, J=6.30 Hz, 2H),4.52-4.74 (m, 1H), 7.36-7.45 (m, 3H), 7.71-7.85 (m, 2H), 7.92 (d, J=8.50Hz, 1H). MS (ESI, pos. ion) m/z 365 [M+H]⁺.

(S)-1-(2-methyl-5-propoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-118)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.73 (t, J=7.33 Hz, 3H), 1.03-1.10 (m,6H), 1.32-1.51 (m, 3H), 2.12 (s, 3H), 2.20-2.45 (m, 2H), 2.89 (dt,J=15.32, 5.09 Hz, 1H), 3.36-3.43 (m, 1H), 3.94 (s, 1H), 4.55-4.72 (m,1H), 6.93 (t, J=6.89 Hz, 1H), 7.18-7.30 (m, 2H), 7.33 (d, J=8.21 Hz,1H), 7.73 (d, J=8.79 Hz, 1H), 8.24 (s, 1H), 8.71 (dd, J=7.04, 0.88 Hz,1H). MS (ESI, pos. ion) m/z 364 [M+H]⁺.

(S)-1-(6-(imidazo[1,2-a]pyridin-2-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-119)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.98-1.08 (m, 6H), 1.21-1.56 (m, 1H),1.78-1.96 (m, 2H), 2.10 (s, 3H), 2.21-2.44 (m, 2H), 2.79-3.00 (m, 1H),3.60-3.78 (m, 2H), 4.44-4.76 (m, 1H), 6.88 (t, J=6.74 Hz, 1H), 7.16-7.30(m, 2H), 7.56 (d, J=9.09 Hz, 1H), 8.04 (d, J=8.50 Hz, 1H), 8.35 (s, 1H),8.65 (d, J=6.74 Hz, 1H). MS (ESI, pos. ion) m/z 364 [M+H]⁺.

(S)-1-(6-(benzo[d]thiazol-2-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-120)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.01-1.15 (m, 6H), 1.43 (m, 2H),1.82-2.04 (m, 2H), 2.15 (s, 3H), 2.29 (br dd, J=12.46, 6.01 Hz, 1H),2.82-2.98 (m, 1H), 3.84 (br t, J=6.45 Hz, 2H), 4.53-4.70 (m, 1H),7.31-7.49 (m, 2H), 7.49-7.61 (m, 1H), 8.05 (d, J=7.92 Hz, 1H), 8.16 (t,J=9.09 Hz, 2H). MS (ESI, pos. ion) m/z 381 [M+H]⁺.

(S)-1-(6-(1H-benzo[d]imidazol-2-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-121)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.88 (t, J=7.33 Hz, 3H), 1.07 (d, J=6.45Hz, 3H), 1.36-1.52 (m, 2H), 1.57-1.79 (m, 2H), 2.15 (s, 3H), 2.22-2.38(m, 1H), 2.90 (dt, J=15.83, 5.86 Hz, 1H), 3.50-3.72 (m, 2H), 4.52-4.78(m, 1H), 7.10-7.25 (m, 2H), 7.33 (br d, J=8.21 Hz, 1H), 7.51-7.60 (m,1H), 7.61-7.70 (m, 1H), 7.83 (d, J=8.50 Hz, 1H), 12.30 (s, 1H). MS (ESI,pos. ion) m/z 364 [M+H]⁺.

(S)-(5-cyclobutoxy-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-122)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.65-0.83 (m, 1H), 0.85-1.06 (m, 2H),1.11-1.22 (m, 4H), 1.23-1.38 (m, 1H), 1.41-1.53 (m, 1H), 1.53-1.69 (m,1H), 1.81-1.94 (m, 1H), 2.15-2.51 (m, 6H), 2.84 (s, 3H), 2.95-2.13 (m,1H), 4.32-4.51 (m, 1H), 4.60-4.79 (m, 1H), 7.33 (d, J=8.40 Hz, 1H),7.85-8.12 (m, 1H). MS (ESI, pos. ion) m/z 384 [M+H]⁺.

(S)-(5-cyclobutoxy-6-(isoxazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-123)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.66-0.72 (m, 1H), 0.76-0.71 (m, 2H),0.98-1.08 (m, 4H), 1.15-1.33 (m, 2H), 1.50-1.58 (m, 1H), 1.74-1.81 (m,1H), 1.96-2.03 (m, 2H), 2.03-2.14 (m, 2H), 2.14-2.33 (m, 2H), 2.89-2.94(m, 1H), 4.10-4.16 (m, 1H), 4.52-4.63 (m, 1H), 7.11 (d, J=8.40 Hz, 1H),7.35 (d, J=8.40 Hz, 1H), 8.73 (s, 1H), 8.96 (s, 1H). MS (ESI, pos. ion)m/z 353 [M+H]⁺.

(S)-(5-cyclobutoxy-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-124)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.76-0.85 (m, 1H), 0.91-1.03 (m, 3H),1.04-1.30 (m, 4H), 1.35-1.47 (m, 1H), 1.61-1.72 (m, 2H), 2.13-2.36 (m,5H), 2.46-2.55 (m, 1H), 3.05-3.13 (m, 2H), 4.20-4.27 (m, 4H), 4.69-4.78(m, 1H), 7.69 (d, J=8.40 Hz, 1H), 8.38 (s, 1H). MS (ESI, pos. ion) m/z385 [M+H]⁺.

(S)-methyl5-cyclobutoxy-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-125)

¹H NMR (400 MHz, CDCl₃) δ ppm 1.21-1.25 (m, 3H), 1.25-1.34 (m, 4H),1.60-1.70 (m, 1H), 2.05-2.20 (m, 4H), 2.26-2.41 (m, 1H), 3.79 (s, 3H),4.13-4.14 (m, 1H), 4.17 (s, 3H), 4.42-4.53 (m, 1H), 7.8 (s, 1H), 8.0 (s,1H). MS (ESI, pos. ion) m/z 375 [M+H]⁺.

(S)-1-(5-cyclobutoxy-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-126)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.11-1.25 (m, 4H), 1.31-1.45 (m, 1H),1.55-1.71 (m, 1H), 1.98-2.55 (m, 9H), 2.97-3.10 (m, 1H), 4.20-4.37 (m,4H), 4.71-4.83 (m, 1H), 7.69 (d, J=11.10 Hz, 1H), 8.37 (s, 1H). MS (ESI,pos. ion) m/z 359 [M+H]⁺.

(S)-(6-(5-amino-1,3,4-thiadiazol-2-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-127)

For(S)-(6-(5-amino-1,3,4-thiadiazol-2-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone,tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate was used as the arylbromide source. The Boc-group was removed as outlined in Example 29,Step 3. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.65-0.80 (m, 1H), 0.87-1.01 (m,2H), 1.09-1.19 (m, 4H), 1.21-1.39 (m, 1H), 1.42-1.59 (m, 1H), 1.68-1.79(m, 1H), 1.82-1.96 (m, 1H), 2.15-2.53 (m, 6H), 2.97-3.10 (m, 1H),4.32-4.54 (m, 1H), 4.60-4.75 (m, 1H), 7.27 (d, J=8.40 Hz, 1H), 7.82-7.94(m, 1H). MS (ESI, pos. ion) m/z 385 [M+H]⁺.

(S)-(5-cyclobutoxy-2-methyl-6-(1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-128)

For(S)-(5-cyclobutoxy-2-methyl-6-(1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone, 1-benzyl-4-bromo-1H-1,2,3-triazole wasused as the aryl bromide source. The benzyl group was removed using thehydrogenation conditions outlined above for Intermediate 1, Step 2. ¹HNMR (300 MHz, CD₃OD) δ ppm 0.65-0.80 (m, 1H), 0.87-0.99 (m, 2H), 1.13(d, J=6.60 Hz, 4H), 1.27-1.39 (m, 2H), 1.53-1.73 (m, 1H), 1.82-1.97 (m,1H), 2.01-2.23 (m, 4H), 2.27-2.44 (m, 2H), 2.99-3.16 (m, 1H), 4.05-4.28(m, 4H), 4.65-4.81 (m, 1H), 7.24 (d, J=7.80 Hz, 1H), 7.72 (d, J=8.40 Hz,1H), 8.15 (s, 1H). MS (ESI, pos. ion) m/z 353 [M+H]⁺.

(S)-methyl-6-(2-carbamoylthiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-129)

¹H NMR (300 MHz, CDCl₃) δ ppm 1.19 (d, J=6.60 Hz, 3H), 1.21-1.32 (m,2H), 1.46-1.56 (m, 1H), 2.01-2.16 (m, 4H), 2.18-2.27 (m, 1H), 2.86-3.00(m, 1H), 3.80 (s, 3H), 4.05-4.13 (m, 1H), 4.55-4.63 (m, 1H), 5.58-5.63(m, 1H), 7.41 (d, J=8.70 Hz, 1H), 7.74 (d, J=8.70 Hz, 1H), 8.03 (s, 1H).MS (ESI, pos. ion) m/z 402 [M+H]⁺.

(S)-methyl5-cyclobutoxy-2-methyl-6-(2-(methylcarbamoyl)thiazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-130)

¹H NMR (300 MHz, CDCl₃) δ ppm 1.16-1.31 (m, 5H), 1.45-1.59 (m, 2H),1.98-2.11 (m, 4H), 2.15-2.28 (m, 1H), 2.45-2.55 (m, 1H), 2.90-2.99 (m,1H), 3.06 (d, J=5.40 Hz, 3H), 3.80 (s, 3H), 4.05-4.14 (m, 1H), 4.55-4.65(m, 1H), 7.41 (d, J=8.70 Hz, 1H), 7.72 (d, J=8.70 Hz, 1H), 7.96 (s, 1H).MS (ESI, pos. ion) m/z 416 [M+H]⁺.

(S)-methyl6-(2-acetamidothiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-131)

¹H NMR (400 MHz, CDCl₃) δ ppm 1.17 (d, J=6.40 Hz, 3H), 1.25-1.36 (m,1H), 1.45-1.66 (m, 1H), 1.67-1.75 (m, 1H), 1.92-1.95 (m 3H), 1.97-2.13(m, 4H), 2.16-2.26 (m, 1H), 2.45-2.51 (m, 1H), 2.90-3.00 (m, 1H), 3.79(s, 3H), 4.13-4.15 (m, 1H), 4.55-4.62 (m, 1H), 7.31-7.37 (m, 2H),7.54-7.57 (m, 1H), 11.6 (br s, 1H). MS (ESI, pos. ion) m/z 416 [M+H]⁺.

Example 36 (S)-methyl5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-132)

Step 1. (S)-methyl6-bromo-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of (S)-methyl6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.050g, 0.167 mmol), 5-chloro-2-fluorobenzonitrile (0.065 g, 0.416 mmol), andcesium carbonate (0.136 g, 0.416 mmol) in DMF (2.0 mL) was heated at100° C. for 16 h. The reaction mixture was cooled to room temperatureand water was added. The mixture was partitioned between ethyl acetateand water. The aqueous phase was separated and extracted with ethylacetate. The combined organic phases were washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated to afford a brownoil. This material was purified via column chromatography on silica gel(Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane)to afford (S)-methyl6-bromo-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.068 g, 94%) as an off-white solid. MS (ESI, pos. ion) m/z 435, 437[M+H]⁺.

Step 2. (S)-methyl6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of (S)-methyl6-bromo-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.068 g, 0.156 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.065 g, 0.172 mmol), XPhos Precatalyst 2nd Generation (0.012 g, 0.016mmol), and cesium carbonate (0.153 g, 0.468 mmol) in dioxane (2.0 mL)and water (0.400 mL) was heated in the microwave at 100° C. for 2 h. Thereaction mixture was filtered through Celite and concentrated to affordan orange oil. This material was purified via column chromatography onsilica gel (Biotage 25 g column, gradient elution with 25-50% ethylacetate-hexane) to afford (S)-methyl6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.057 g, 60%) as an off-white solid. MS (ESI, pos. ion) m/z 606 [M+H]⁺.

Step 3. (S)-methyl5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of(S)-methyl6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.057 g, 0.094 mmol) in dichloromethane (2.0 mL) and the reactionmixture stirred at rt for 1.5 h. The reaction mixture was concentratedand the residue was partitioned between dichloromethane and saturatedaqueous sodium bicarbonate solution. The organic phase was separated,dried over anhydrous sodium sulfate, filtered, and concentrated toafford (S)-methyl5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.041 g, 86%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.01-1.09 (m, 4H), 1.49-1.79 (m, 4H), 1.80-2.07 (m, 4H), 2.52-2.63 (m,2H), 2.99 (br d, J=12.31 Hz, 2H), 3.72 (s, 3H), 4.03-4.23 (m, 1H),4.45-4.70 (m, 1H), 6.44 (br d, J=9.09 Hz, 1H), 7.47-7.64 (m, 3H), 7.67(s, 1H), 7.95 (s, 1H), 8.10 (d, J=2.35 Hz, 1H). MS (ESI, pos. ion) m/z506 [M+H]⁺.

The following examples were made according to the procedure outlined forExample 36:

(S)-methyl5-(2-cyano-4-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-133)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00-1.12 (m, 4H), 1.48-1.79 (m, 4H),1.79-2.05 (m, 4H), 2.51-2.61 (m, 2H), 2.98 (br d, J=12.31 Hz, 2H), 3.72(s, 3H), 3.99-4.23 (m, 1H), 4.38-4.67 (m, 1H), 6.43 (br d, J=5.28 Hz,1H), 7.37 (td, J=8.79, 3.22 Hz, 1H), 7.54-7.70 (m, 3H), 7.89-7.98 (m,2H). MS (ESI, pos. ion) m/z 490 [M+H]⁺.

(S)-methyl5-(2-chloro-4-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-134)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.06 (br d, J=1.76 Hz, 4H), 1.43-1.75(m, 4H), 1.77-2.08 (m, 4H), 2.52-2.68 (m, 2H), 2.98 (br d, J=12.02 Hz,2H), 3.72 (s, 3H), 4.09 (br t, J=12.02 Hz, 1H), 4.44-4.73 (m, 1H),6.27-6.66 (m, 1H), 7.50-7.65 (m, 3H), 7.67 (s, 1H), 7.95 (s, 1H), 8.22(s, 1H). MS (ESI, pos. ion) m/z 506 [M+H]⁺.

(S)-methyl5-(4-cyano-2-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-135)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00-1.12 (m, 4H), 1.50-1.76 (m, 4H),1.79-2.09 (m, 4H), 2.47-2.64 (m, 2H), 2.99 (br d, J=12.61 Hz, 2H), 3.72(s, 3H), 4.01-4.21 (m, 1H), 4.44-4.70 (m, 1H), 6.52 (br t, J=8.65 Hz,1H), 7.37-7.71 (m, 4H), 7.94 (s, 1H), 8.05 (br d, J=11.14 Hz, 1H). MS(ESI, pos. ion) m/z 490 [M+H]⁺.

(S)-2-(1-acetyl-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(I-136)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.16 (d, J=6.60 Hz, 3H), 1.47 (br s, 1H),1.78-1.93 (m, 2H), 2.01-2.09 (m, 2H), 2.15-2.35 (m, 5H), 2.55-2.83 (m,3H), 3.10-3.21 (m, 2H), 4.18-4.32 (m, 1H), 4.78 (br s, 1H), 6.50 (d,J=8.10 Hz, 1H), 7.11 (t, J=7.80 Hz, 1H), 7.35-7.50 (m, 2H), 7.61 (d,J=8.40 Hz, 1H), 7.71-7.79 (m, 2H), 7.99 (s, 1H). MS (ESI, pos. ion) m/z456 [M+H]⁺.

methyl(S)-5-(2-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-137)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.06 (d, J=6.40 Hz, 3H), 1.48-1.55 (m,1H), 1.65-1.74 (m, 1H), 1.85-2.05 (m, 3H), 2.20-2.85 (m, 4H), 2.95-3.05(m, 2H), 3.72 (s, 3H), 4.05-4.15 (m, 1H), 4.50-4.60 (m, 1H), 6.30-6.40(m, 1H), 6.93-6.99 (m, 1H), 7.23-7.30 (m, 1H), 7.43 (d, J=8.80 Hz, 1H),7.50-7.60 (m, 1H), 7.59-7.65 (m, 2H), 7.79 (s, 1H). MS (ESI, pos. ion)m/z 472 [M+H]⁺.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-138)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00 (br d, J=6.45 Hz, 3H), 1.39-1.62(m, 2H), 1.83-2.00 (m, 2H), 3.29-3.51 (m, 2H), 3.55-3.63 (m, 1H), 3.66(s, 3H), 3.70-3.82 (m, 1H), 4.52 (m, 1H), 4.80 (br d, J=7.04 Hz, 1H),4.95-5.16 (m, 1H), 6.37 (br d, J=8.50 Hz, 1H), 6.94-7.20 (m, 1H), 7.42(q, J=7.52 Hz, 1H), 7.55 (m, 2H), 7.65-7.75 (m, 1H), 7.75-7.90 (m, 1H),7.93-8.12 (m, 1H) MS (ESI, pos. ion) m/z 444 [M+H]⁺.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2-cyano-3-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-139)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00 (br d, J=5.86 Hz, 3H), 1.45-1.67(m, 2H), 1.81-1.99 (m, 2H), 3.29-3.51 (m, 2H), 3.66 (s, 3H), 3.73-4.02(m, 2H), 4.40-4.65 (m, 1H), 4.82 (m, 1H), 4.98-5.27 (m, 1H), 6.25 (br d,J=7.33 Hz, 1H), 7.08 (br t, J=8.79 Hz, 1H), 7.38-7.64 (m, 3H), 7.72 (brd, J=6.16 Hz, 1H), 7.89-8.10 (m, 1H). MS (ESI, pos. ion) m/z 462 [M+H]⁺.

(S)-4-(1-acetyl-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(I-140)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.15 (d, J=6.60 Hz, 3H), 1.20-1.45 (m,1H), 1.80-1.95 (m, 2H), 1.97-2.05 (m, 2H), 2.10-2.25 (m, 5H), 2.52-2.69(m, 1H), 2.72-2.82 (m, 2H), 3.20 (d, J=12.90 Hz, 2H), 4.15-4.25 (m, 1H),4.65-4.82 (m, 1H), 6.93 (d, J=8.70 Hz, 2H), 7.38 (br s, 1H), 7.62 (t,J=9.00 Hz, 3H), 7.75 (s, 1H), 7.93 (s, 1H). MS (ESI, pos. ion) m/z 456[M+H]⁺.

(S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)pyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-141)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.15 (s, 3H), 1.20-1.50 (m, 1H), 1.72-1.87(m, 2H), 1.95-2.05 (m, 2H), 2.07-2.45 (m, 6H), 2.65-2.75 (m, 2H),3.05-3.15 (m, 2H), 4.10-4.22 (m, 1H), 4.79 (br s, 1H), 7.15-7.37 (m,2H), 7.56 (d, J=8.40 Hz, 1H), 7.71 (s, 1H), 7.86 (s, 1H), 8.12-8.19 (m,2H). MS (ESI, pos. ion) m/z 500 [M+H]⁺.

(S)-1-(5-(3-chloropyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-142)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.16 (d, J=6.60 Hz, 3H), 1.45 (br s, 1H),1.75-1.92 (m, 2H), 1.97-2.10 (m, 2H), 2.15-2.32 (m, 5H), 2.50-2.70 (m,1H), 2.69-2.78 (m, 2H), 3.08-3.15 (m, 2H), 4.08-4.21 (m, 1H), 4.72-4.91(m, 1H), 6.95-7.05 (m, 1H), 7.25-7.35 (m, 1H), 7.55 (d, J=8.10 Hz, 1H),7.77 (s, 1H), 7.85-7.95 (m, 2H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z466 [M+H]⁺.

(S)-2-(1-acetyl-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)nicotinonitrile(I-143)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (d, J=6.80 Hz, 3H), 1.38-1.55 (m,1H), 1.79-1.92 (m, 2H), 1.98-2.09 (m, 2H), 2.15-2.41 (m, 5H), 2.52-2.70(m, 1H), 2.70-2.79 (m, 2H), 3.10-3.18 (m, 2H), 4.18-4.28 (m, 1H),4.70-4.85 (m, 1H), 7.12-7.18 (m, 1H), 7.20-7.39 (m, 1H), 7.53 (d, J=8.40Hz, 1H), 7.74 (s, 1H), 7.95 (s, 1H), 8.11-8.22 (m, 2H). MS (ESI, pos.ion) m/z 457 [M+H]⁺.

(S)-1-(2-methyl-5-(5-methylpyrimidin-2-yloxy)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-144)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.02 (d, J=6.80 Hz, 3H), 1.25-1.35 (m,1H), 1.65-1.78 (m, 2H), 1.85-95 (m, 2H), 2.01-2.21 (m, 8H), 2.45-2.65(m, 3H), 2.98-3.059 (m, 2H), 4.05-4.12 (m, 1H), 4.58-4.75 (m, 1H),7.05-7.20 (m, 1H), 7.43 (d, J=8.40 Hz, 1H), 7.66 (s, 1H), 7.87 (s, 1H),8.27 (s, 2H). MS (ESI, pos. ion) m/z 447 [M+H]⁺.

(S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(pyrazin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-145)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.05 (d, J=6.40 Hz, 3H), 1.20-1.45 (m,1H), 1.65-1.80 (m, 2H), 1.82-1.89 (m, 2H), 2.05-2.25 (m, 5H), 2.48-2.65(m, 3H), 2.95-3.05 (m, 2H), 4.05-4.15 (m, 1H), 4.60-4.78 (m, 1H),7.10-7.25 (m, 1H), 7.43 (d, J=8.40 Hz, 1H), 7.61 (s, 1H), 7.84 (s, 1H),7.92 (s, 1H), 8.10 (d, J=2.80 Hz, 1H), 8.38 (s, 1H). MS (ESI, pos. ion)m/z 433 [M+H]⁺.

(S)-methyl5-(4-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-146)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.17 (d, J=6.30 Hz, 3H), 1.52-1.65 (m,1H), 1.75-1.95 (m, 2H), 1.97-2.15 (m, 3H), 2.38-2.48 (m, 1H), 2.55-2.78(m, 3H), 3.08-3.15 (m, 2H), 3.83 (s, 1H), 4.15-4.29 (m, 1H), 4.65-4.72(m, 1H), 6.89-6.99 (m, 2H), 7.53-7.70 (m, 5H), 7.92 (s, 1H). MS (ESI,pos. ion) m/z 472 [M+H]⁺.

(S)-methyl5-(3-cyanopyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-147)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.18 (d, J=6.80 Hz, 3H), 1.59-1.68 (m,1H), 1.80-1.95 (m, 2H), 1.99-2.15 (m, 3H), 2.30-2.70 (br m, 2H),2.70-2.80 (m, 2H), 3.10-3.19 (m, 2H), 3.83 (s, 3H), 4.15-4.25 (m, 1H),4.65-4.71 (m, 1H), 7.11-7.15 (m, 1H), 7.45 (d, J=8.80 Hz, 1H), 7.61 (d,J=8.80 Hz, 1H), 7.71 (s, 1H), 7.91 (s, 1H), 8.12-8.21 (m, 2H). MS (ESI,pos. ion) m/z 473 [M+H]⁺.

(S)-methyl5-(2-cyano-3-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-148)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.19 (d, J=6.60 Hz, 3H), 1.58-1.72 (m,1H), 1.78-1.99 (m, 2H), 1.98-2.15 (m, 3H), 2.68-2.82 (m, 2H), 3.07-3.19(m, 2H), 4.20-4.30 (m, 1H), 4.60-4.75 (m, 1H), 6.25-6.35 (m, 1H), 6.96(t, J=8.40 Hz, 1H), 7.39-7.55 (m, 2H), 7.65-7.71 (m, 1H), 7.76 (s, 1H),7.95 (s, 1H). MS (ESI, pos. ion) m/z 490 [M+H]⁺.

(S)-methyl5-(3-chloro-2-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-149)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.05-1.20 (m, 3H), 1.58-1.72 (m, 1H),1.79-1.95 (m, 2H), 1.98-2.15 (m, 3H), 2.20-2.70 (br s, 1H), 2.65-2.80(m, 3H), 3.05-3.15 (m, 2H), 3.82 (s, 3H), 4.15-4.25 (m, 1H), 4.60-4.75(m, 1H), 6.30-6.50 (m, 1H), 7.20 (d, J=8.10 Hz, 1H), 7.38 (t, J=8.40 Hz,1H), 7.52 (d, J=8.70 Hz, 1H), 7.60-7.75 (m, 2H), 7.93 (s, 1H). MS (ESI,pos. ion) m/z 506 [M+H]⁺.

(S)-2-(1-(cyclopropanecarbonyl)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(I-150)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.75-0.90 (m, 1H), 0.95-1.05 (m, 2H),1.15-1.30 (m, 4H), 1.45-1.65 (m, 1H), 1.81-1.99 (m, 2H), 2.01-2.13 (m,3H), 2.20-2.60 (m, 2H), 2.65-2.82 (m, 3H), 3.10-3.21 (m, 2H), 4.20-4.35(m, 1H), 4.80-4.95 (m, 1H), 6.50-6.64 (m, 1H), 7.18 (t, J=7.50 Hz, 1H),7.45-7.55 (m, 2H), 7.67 (d, J=8.40 Hz, 1H), 7.78-7.82 (m, 2H), 8.03 (s,1H). MS (ESI, pos. ion) m/z 483 [M+H]⁺.

(S)-2-(1-(cyclopropanecarbonyl)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)-6-fluorobenzonitrile(I-151)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.82 (m, 1H), 0.85-1.01 (m, 2H),1.10-1.21 (m, 4H), 1.45-1.60 (m, 1H), 1.79-1.92 (m, 2H), 1.95-2.10 (m,3H), 2.15-2.30 (m, 1H), 2.30-2.50 (m, 1H), 2.65-2.79 (m, 3H), 3.08-3.19(m, 2H), 4.15-4.30 (m, 1H), 4.78-4.90 (m, 1H), 6.30-6.40 (m, 1H),6.90-7.00 (m, 1H), 7.40-7.50 (m, 2H), 7.62 (d, J=8.40 Hz, 1H), 7.78 (s,1H), 7.98 (s, 1H). MS (ESI, pos. ion) m/z 500 [M+H]⁺.

(S)-4-(1-(cyclopropanecarbonyl)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)-3-fluorobenzonitrile(I-152)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.65-0.70 (m, 1H), 0.78-0.92 (m, 2H),0.99-1.11 (m, 4H), 1.30-1.42 (m, 1H), 1.65-1.80 (m, 2H), 1.85-1.95 (m,3H), 2.08-2.19 (m, 1H), 2.20-2.30 (m, 1H), 2.50-2.65 (m, 3H), 2.95-3.05(m, 2H), 4.05-4.15 (m, 1H), 4.65-4.75 (m, 1H), 6.51 (t, J=8.40 Hz, 1H),7.24 (d, J=8.80 Hz, 1H), 7.36 (d, J=8.40 Hz, 1H), 7.51 (d, J=8.40 Hz,1H), 7.60-7.70 (m, 2H), 7.80 (s, 1H). MS (ESI, pos. ion) m/z 500 [M+H]⁺.

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(I-153)

(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrilewas synthesized according to the procedures described above for Example36, with the following changes: (1) in Step 2,1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewas used in place of tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(3) Step 3 (removal of the Boc-protecting group) was eliminated. ¹H NMR(300 MHz, CD₃OD) δ ppm 0.92-1.05 (m, 4H), 1.16 (d, J=6.30 Hz, 3H),1.35-1.52 (m, 1H), 2.10-2.40 (m, 5H), 2.58-2.80 (m, 1H), 3.55-3.65 (m,1H), 4.68-4.89 (m, 1H), 6.40-6.55 (m, 1H), 7.05-7.15 (m, 1H), 7.30-7.52(m, 2H), 7.55-7.65 (m, 1H), 7.70-7.80 (m, 2H), 7.96 (s, 1H). MS (ESI,pos. ion) m/z 413 [M+H]⁺.

Example 37(S)-2-(1-(cyclopropanecarbonyl)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(I-154)

Step 1.(S)-2-(1-(cyclopropanecarbonyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile

A mixture of(S)-2-(6-bromo-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(0.70 g, 0.17 mmol, 1.00 equiv), bis(pinacolato)diboron (0.216 g, 0.85mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.015 g, 0.02 mmol), potassium acetate (0.042 g,0.43 mmol) in 1,4-dioxane (10 mL) was stirred overnight at 90° C. Themixture was cooled to room temperature, diluted with ethyl acetate (50mL), washed with water (20 mL) and brine (20 mL), dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified via column chromatography on silica gel (eluting with 25% ethylacetate-petroleum ether) to afford(S)-2-(1-(cyclopropanecarbonyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(0.050 g, 64%) as yellow oil. MS (ESI, pos. ion) m/z 459[M+H]⁺.

Step 2.(S)-2-(1-(cyclopropanecarbonyl)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile

A mixture of(S)-2-(1-(cyclopropanecarbonyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(0.050 g, 0.11 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (0.025 g, 0.15mmol), cesium carbonate (0.110 g, 0.34 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.10 g, 0.01 mmol) in 1,4-dioxane(10 mL) andwater (3 mL) was stirred overnight at 80° C. The reaction mixture wascooled to room temperature and filtered through a short pad of Celite.The filtrate was concentrated and purified via preparative thin layerchromatography (eluting with 25% ethyl acetate-petroleum ether) toafford(S)-2-(1-(cyclopropanecarbonyl)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(0.006 g, 13%) as a white solid. MS (ESI, pos. ion) m/z 414[M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ ppm 0.75-0.82 (m, 1H), 0.88-1.05 (m, 2H),1.15-1.25 (m, 3H), 1.28-1.35 (m, 1H), 1.45-1.55 (m, 1H), 1.97-2.05 (m,1H), 2.15-2.25 (m, 1H), 2.27-2.45 (m, 1H), 2.60-2.75 (m, 1H), 4.09 (s,3H), 4.75-4.85 (m, 1H), 6.58 (d, J=8.40 Hz, 1H), 7.17 (t, J=8.00 Hz,1H), 7.45-7.51 (m, 1H), 7.57 (d, J=8.40 Hz, 1H), 7.78 (d, J=1.20 Hz,1H), 8.03-8.07 (m, 2H). MS (ESI, pos. ion) m/z 414[M+H]⁺.

Example 38(S)-4-(1-acetyl-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide(I-155)

Step 1.4-[[(2S)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy]benzamide

A 100-mL round-bottom flask equipped with a balloon filled with air wascharged with1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(0.300 g, 1.06 mmol), (4-carbamoylphenyl)boronic acid (0.437 g, 2.65mmol), copper acetate (0.386 g, 2.12 mmol), pyridine (1 mL),dichloromethane (40 mL), and 4 Å molecular sieves (4.0 g). The resultingmixture stirred for 3 days at room temperature. The reaction mixture wasfiltered through a pad of Celite, and the filtrate was concentratedunder vacuum. The residue was purified by preparative thin layerchromatography (eluting with 20-25% ethyl acetate-petroleum ether) toafford4-[[(2S)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy]benzamide(0.148 g, 35%) as a yellow oil. MS (ESI, pos. ion) m/z 403, 405 [M+H]⁺.

Step 2. tert-butyl4-[4-[(2S)-1-acetyl-5-(4-carbamoylphenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]piperidine-1-carboxylate

A mixture of4-[[(2S)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy]benzamide(0.080 g, 0.20 mmol), tert-butyl4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(0.090 g, 0.24 mmol), potassium carbonate (0.082 g, 0.59 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.016 g, 0.02 mmol) in 1,4-dioxane (20 mL) andwater (2 mL) stirred overnight at 100° C. The reaction mixture wascooled to room temperature, filtered through a pad of Celite, andconcentrated under vacuum. The residue was purified via preparative thinlayer chromatography (eluting with 50% ethyl acetate-petroleum ether) toafford tert-butyl4-[4-[(2S)-1-acetyl-5-(4-carbamoylphenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]piperidine-1-carboxylate(0.080 g, 70%) as a yellow oil. MS (ESI, pos. ion) m/z 574 [M+H]⁺.

Step 3.(S)-4-(1-acetyl-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide

Trifluoroacetic acid (3.5 mL) was added to a solution of tert-butyl4-[4-[(2S)-1-acetyl-5-(4-carbamoylphenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]piperidine-1-carboxylate(0.080 g, 0.14 mmol) in dichloromethane (30 mL). The reaction mixturestirred for 2 h at room temperature and was then concentrated undervacuum. The residue was dissolved in dichloromethane (50 mL), washedwith saturated aqueous potassium carbonate solution (3×20 mL) and brine(20 mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue was purified by preparative-HPLC with thefollowing conditions (Prep-HPLC-12): Column, XBridge Prep C18 OBDColumn, 19×150 mm 5 um 13 nm; mobile phase: water (0.05% ammoniumbicarbonate) and acetonitrile (20% to 95% acetonitrile in 18 min, flowrate: 20 mL/min); Detector, UV 254/220 nm. This afforded4-[[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy]benzamide(0.033 g, 50%) as an off-white solid.

¹H NMR (300 MHz, CD₃OD) δ ppm 1.15 (d, J=6.60 Hz, 3H), 1.25-1.45 (m,1H), 1.72-1.92 (m, 2H), 1.95-2.05 (m, 2H), 2.15-2.40 (m, 5H), 2.60-2.80(m, 3H), 3.05-3.15 (m, 2H), 4.15-4.25 (m, 1H), 4.79 (br s, 1H), 6.87 (d,J=8.70 Hz, 2H), 7.38 (br s, 1H), 7.64 (d, J=8.70 Hz, 1H), 7.75-7.89 (m,3H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 474 [M+H]⁺.

The following examples were made according to the procedure outlined forExample 38:

(S)-1-(5-(3-methoxyphenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-156)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.11 (d, J=6.60 Hz, 3H), 1.22-1.42 (m,1H), 1.75-1.89 (m, 2H), 1.98-2.08 (m, 2H), 2.23 (s, 3H), 2.14-2.35 (m,2H), 2.64-2.79 (m, 3H), 3.09-3.18 (m, 2H), 3.72 (s, 3H), 4.15-4.25 (m,1H), 4.68-4.83 (m, 1H), 6.28-35 (m, 2H), 6.52-6.57 (m, 1H), 7.14 (t,J=8.10 Hz, 1H), 7.20-7.35 (m, 1H), 7.61 (d, J=8.40 Hz, 1H), 7.80 (s,1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 461 [M+H]⁺.

(S)-1-(5-(2-chlorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-157)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (d, J=6.80 Hz, 3H), 1.30-1.45 (m,1H), 1.75-1.89 (m, 2H), 1.95-2.05 (m, 2H), 2.15-2.35 (m, 5H), 2.55-2.79(m, 3H), 3.09-3.15 (m, 2H), 4.12-4.22 (m, 1H), 4.78 (br s, 1H),6.30-6.35 (m, 1H), 6.89-6.97 (m, 1H), 6.99-7.05 (m, 1H), 7.37 (br s,1H), 7.42-7.49 (m, 1H), 7.64 (d, J=8.40 Hz, 1H), 7.83 (s, 1H), 8.01 (s,1H). MS (ESI, pos. ion) m/z 465 [M+H]⁺.

(S)-methyl5-(4-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-158)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.14 (d, J=6.60 Hz, 3H), 1.48-1.62 (m,1H), 1.75-1.91 (m, 2H), 1.95-2.15 (m, 3H), 2.35-2.45 (m, 1H), 2.55-2.78(m, 3H), 3.09-3.18 (m, 2H), 4.15-4.25 (m, 1H), 4.55-4.68 (m, 1H),6.68-6.78 (m, 2H), 6.91-7.02 (m, 2H), 7.49-7.52 (m, 2H), 7.76 (s, 1H),7.92 (s, 1H). MS (ESI, pos. ion) m/z 465 [M+H]⁺.

(S)-methyl5-(4-chlorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-159)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.15 (d, J=6.60 Hz, 3H), 1.50-1.62 (m,1H), 1.75-1.92 (m, 2H), 1.97-2.15 (m, 3H), 2.35-2.48 (m, 1H), 2.52-2.82(m, 3H), 3.09-3.18 (m, 2H), 4.15-4.25 (m, 1H), 4.55-4.72 (m, 1H), 6.77(d, J=8.70 Hz, 2H), 7.24 (d, J=9.00 Hz, 2H), 7.45-7.55 (m, 2H), 7.77 (s,1H), 7.92 (s, 1H). MS (ESI, pos. ion) m/z 481 [M+H]⁺.

(S)-methyl5-(2-chlorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-160)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.15 (d, J=6.60 Hz, 3H), 1.52-1.68 (m,1H), 1.72-1.92 (m, 2H), 1.95-2.15 (m, 4H), 2.65-2.80 (m, 3H), 3.05-3.18(m, 2H), 3.81 (s, 3H), 4.12-4.25 (m, 1H), 4.55-4.75 (m, 1H), 6.28-6.35(m, 1H), 6.85-6.95 (m, 1H), 6.95-7.05 (m, 1H), 7.42-7.65 (m, 3H), 7.79(s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 481 [M+H]⁺.

(S)-methyl5-(4-carbamoylphenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-161)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (d, J=6.40 Hz, 3H), 1.52-1.62 (m,1H), 1.83-1.95 (m, 2H), 1.99-2.13 (m, 3H), 2.42-2.49 (m, 1H), 2.55-2.65(m, 1H), 2.78-2.85 (m, 2H), 3.15-3.22 (m, 2H), 3.83 (s, 3H), 4.19-4.25(m, 1H), 4.62-4.65 (m, 1H), 6.84 (d, J=8.80 Hz, 2H), 7.50-7.60 (m, 2H),7.75-7.82 (m, 3H), 7.91 (s, 1H). MS (ESI, pos. ion) m/z 490 [M+H]⁺.

(S)-methyl5-(3-cyano-4-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-162)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (d, J=6.80 Hz, 3H), 1.55-1.65 (m,1H), 1.80-1.98 (m, 2H), 1.99-2.12 (m, 3H), 2.39-2.48 (m, 1H), 2.60-2.80(m, 3H), 3.10-3.20 (m, 2H), 3.82 (s, 3H), 4.19-4.30 (m, 1H), 4.60-4.70(m, 1H), 7.05-7.22 (m, 3H), 7.50-7.62 (m, 2H), 7.75 (s, 1H), 7.94 (s,1H). MS (ESI, pos. ion) m/z 490 [M+H]⁺.

(S)-methyl5-(3-chloro-4-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-163)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.17 (d, J=6.60 Hz, 3H), 1.52-1.65 (m,1H), 1.78-1.95 (m, 2H0, 1.97-2.15 (m, 3H), 2.38-2.45 (m, 1H), 2.58-2.79(m, 3H), 3.09-3.15 (m, 2H), 3.83 (s, 3H), 4.15-4.30 (m, 1H), 4.60-4.72(m, 1H), 6.68-6.72 (m, 1H), 6.85-6.89 (m, 1H), 7.13 (t, J=9.00 Hz, 1H),7.52-7.63 (m, 2H), 7.76 (s, 1H), 7.95 (s, 1H). MS (ESI, pos. ion) m/z499 [M+H]⁺.

(S)-cyclopropyl(5-(4-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-164)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.65-0.82 (m, 1H), 0.85-1.01 (m, 2H),1.01-1.19 (m, 4H), 1.30-1.45 (m, 1H), 1.75-1.90 (m, 2H), 1.90-2.05 (m,3H), 2.09-2.35 (m, 2H), 2.60-2.80 (m, 3H), 3.05-3.20 (m, 2H), 4.11-4.28(m, 1H), 4.70-4.82 (m, 1H), 6.79 (s, 1H), 6.90-7.03 (m, 2H), 7.39 (d,J=8.00 Hz, 1H), 7.62 (d, J=8.00 Hz, 1H), 7.79 (s, 1H), 7.96 (s, 1H). MS(ESI, pos. ion) m/z 475 [M+H]⁺.

(S)-(5-(2-chlorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-165)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.72-0.82 (m, 1H), 0.90-1.05 (m, 2H),1.10-1.25 (m, 4H), 1.40-1.50 (m, 1H), 1.78-1.95 (m, 2H), 1.95-2.10 (m,3H), 2.20-2.40 (m, 2H), 2.70-2.90 (m, 3H), 3.10-3.18 (m, 2H), 4.15-4.25(m, 1H), 4.75-4.85 (m, 1H), 6.35-6.42 (m, 1H), 6.90-6.98 (m, 1H),7.01-7.09 (m, 1H), 7.40-7.50 (m, 2H), 7.65 (d, J=8.40 Hz, 1H), 7.84 (s,1H), 8.01 (s, 1H). MS (ESI, pos. ion) m/z 491 [M+H]⁺.

(S)-(5-(4-chlorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-166)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.72-0.80 (m, 1H), 0.85-1.05 (m, 2H),1.10-1.19 (m, 4H), 1.35-1.45 (m, 1H), 1.75-1.90 (m, 2H), 1.95-2.05 (m,3H), 2.15-2.35 (m, 2H), 2.65-2.79 (m, 3H), 3.10-3.20 (m, 2H), 4.15-4.30(m, 1H), 4.75-4.85 (m, 1H), 6.80 (dd, J=10.80, 2.00 Hz, 2H), 7.26 (dd,J=10.80, 2.00 Hz, 2H), 7.40 (d, J=8.40 Hz, 1H), 7.63 (d, J=8.40 Hz, 1H),7.79 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 491 [M+H]⁺.

(S)-4-(1-(cyclopropanecarbonyl)-2-methyl-6-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(I-167)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.69-0.80 (m, 1H), 0.83-1.01 (m, 2H),1.09-1.22 (m, 4H), 1.30-1.50 (m, 1H), 1.70-1.90 (m, 2H), 1.90-2.01 (m,3H), 2.11-2.35 (m, 2H), 2.60-2.75 (m, 3H), 3.03-3.12 (m, 2H), 4.10-4.25(m, 1H), 4.70-4.85 (m, 1H), 6.95 (d, J=8.70 Hz, 2H), 7.41 (d, J=8.40 Hz,2H), 7.55-7.68 (m, 3H), 7.73 (s, 1H), 7.92 (s, 1H). MS (ESI, pos. ion)m/z 491 [M+H]⁺.

(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-168)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.80 (m, 1H), 0.90-1.01 (m, 2H),1.10-1.20 (m, 4H), 1.32-1.45 (m, 1H), 1.75-1.92 (m, 2H), 1.95-2.05 (m,3H), 2.15-2.35 (m, 2H), 2.65-2.75 (m, 3H), 3.05-3.15 (m, 2H), 4.10-4.25(m, 1H), 4.70-4.82 (m, 1H), 6.80 (d, J=8.00 Hz, 2H), 6.98 (t, J=7.20 Hz,1H), 7.28 (t, J=8.00 Hz, 2H), 7.39 (d, J=8.40 Hz, 1H), 7.80 (s, 1H),7.98 (s, 1H). MS (ESI, pos. ion) m/z 457 [M+H]⁺.

(S)-(5-(3-chloro-4-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-169)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.62-0.72 (m, 1H), 0.78-0.90 (m, 2H),0.98-1.10 (m, 4H), 1.25-1.35 (m, 1H), 1.68-1.80 (m, 2H), 1.85-1.95 (m,3H), 2.09-2.25 (m, 2H), 2.55-2.70 (m, 3H), 2.95-3.05 (m, 2H), 4.05-4.15(m, 1H), 4.65-4.75 (m, 1H), 6.55-6.65 (m, 1H), 6.75-6.85 (m, 1H), 7.03(t, J=8.80 Hz, 1H), 7.31 (d, J=8.40 Hz, 1H), 7.51 (d, J=8.40 Hz, 1H),7.67 (s, 1H), 7.83 (s, 1H). MS (ESI, pos. ion) m/z 509 [M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-170)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.58-0.70 (m, 1H), 0.78-0.92 (m, 2H),0.95-1.10 (m, 4H), 1.20-1.30 (m, 1H), 1.80-1.90 (m, 1H), 2.05-2.18 (m,2H), 2.55-2.65 (m, 1H), 3.75-3.85 (m, 2H), 3.88-3.95 (m, 2H), 4.60-4.70(m, 1H), 5.01-5.12 (m, 1H), 6.65-6.70 (m, 2H), 6.85-6.90 (m, 2H), 7.28(d, J=8.40 Hz, 1H), 7.51 (d, J=8.40 Hz, 1H), 7.77 (s, 1H), 7.93 (s, 1H).MS (ESI, pos. ion) m/z 447 [M+H]⁺.

(S)-cyclopropyl(5-(3-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-171)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.62-0.72 (m, 1H), 0.78-0.90 (m, 2H),0.95-1.10 (m, 4H), 1.20-1.35 (m, 1H), 1.68-1.80 (m, 2H), 1.85-1.95 (m,3H), 2.05-2.25 (m, 2H), 2.55-2.70 (m, 3H), 2.95-3.10 (m, 2H), 4.05-4.15(m, 1H), 4.65-4.70 (m, 1H), 6.40-6.52 (m, 2H), 6.55-6.65 (m, 1H),7.10-7.15 (m, 1H), 7.30 (d, J=8.40 Hz, 1H), 7.52 (d, J=8.40 Hz, 1H),7.69 (s, 1H), 7.85 (s, 1H). MS (ESI, pos. ion) m/z 475 [M+H]⁺.

(S)-cyclopropyl(5-(3,4-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-172)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.65-0.70 (m, 1H), 0.75-0.90 (m, 2H),0.95-1.10 (m, 4H), 1.25-1.35 (m, 1H), 1.65-1.80 (m, 2H), 1.85-1.95 (m,3H), 2.05-2.25 (m, 2H), 2.55-2.65 (m, 3H), 2.95-3.05 (m, 2H), 4.05-4.18(m, 1H), 4.65-4.75 (m, 1H), 6.40-6.50 (m, 1H), 6.55-6.70 (m, 1H),6.95-7.10 (m, 1H), 7.30 (d, J=8.40 Hz, 1H), 7.51 (d, J=8.40 Hz, 1H),7.68 (s, 1H), 7.86 (s, 1H). MS (ESI, pos. ion) m/z 493 [M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3-fluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-173)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.65-0.72 (m, 1H), 0.75-0.90 (m, 2H),0.95-1.10 (m, 4H), 1.20-1.35 (m, 1H), 1.85-1.95 (m, 1H), 2.05-2.25 (m,2H), 2.55-2.65 (m, 1H), 3.55-3.70 (m, 1H), 3.75-3.85 (m, 1H), 3.90-3.98(m, 1H), 4.65-4.72 (m, 1H), 5.05-5.12 (m, 1H), 6.40-6.50 (m, 2H),6.55-6.70 (m, 1H), 7.05-7.15 (m, 1H), 7.25-7.30 (m, 1H), 7.53 (d, J=8.40Hz, 1H), 7.70-7.79 (m, 1H), 7.90-8.00 (m, 1H). MS (ESI, pos. ion) m/z447 [M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-174)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.60-0.70 (m, 1H), 0.75-0.90 (m, 2H),0.95-1.10 (m, 4H), 1.20-1.35 (m, 1H), 1.85-1.90 (m, 1H), 2.05-2.22 (m,2H), 2.55-2.62 (m, 1H), 3.75-3.85 (m, 2H), 3.92-3.98 (m, 2H), 4.65-4.70(m, 1H), 5.05-5.15 (m, 1H), 6.40-6.50 (m, 1H), 6.60-6.68 (m, 1H),6.95-7.05 (m, 1H), 7.30 (d, J=8.40 Hz, 1H), 7.52 (d, J=8.00 Hz, 1H),7.77 (s, 1H), 7.93 (s, 1H). MS (ESI, pos. ion) m/z 465 [M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-175)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.80 (m, 1H), 0.85-1.02 (m, 2H),1.10-1.20 (m, 4H), 1.30-1.40 (m, 1H), 1.92-2.02 (m, 1H), 2.12-2.32 (m,2H), 2.65-2.75 (m, 1H), 4.48 (d, J=7.60, 4 H), 4.75-4.81 (m, 1H),5.30-41 (m, 1H), 6.75-6.82 (m, 2H), 6.95-7.01 (m, 1H), 7.23-7.29 (m,2H), 7.40 (d, J=8.40 Hz, 1H), 7.64 (d, J=8.40 Hz, 1H), 7.98 (s, 1H),8.03 (s, 1H). MS (ESI, pos. ion) m/z 429 [M+H]⁺.

(S)-methyl5-(3,4-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-176)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.04 (d, J=6.40 Hz, 3H), 1.45-1.52 (m,1H), 1.68-1.82 (m, 2H), 1.87-2.02 (m, 3H), 2.25-2.35 (m, 1H), 2.45-2.70(m, 3H), 3.00-3.10 (m, 2H), 3.70 (s, 3H), 4.05-4.15 (m, 1H), 4.48-4.55(m, 1H), 6.35-6.42 (m, 1H), 6.55-6.65 (m, 1H), 6.95-7.05 (m, 1H),7.45-7.55 (m, 2H), 7.65 (s, 1H), 7.80 (s, 1H). MS (ESI, pos. ion) m/z483 [M+H]⁺.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3-chlorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-177)

¹H NMR (300 MHz, DMSO-d6) δ ppm 1.06 (d, J=6.60 Hz, 3H), 1.46-1.67 (m,1H), 1.89-2.09 (m, 1H), 2.37-2.48 (m, 2H), 3.60-3.90 (m, 7H), 4.45-4.70(m, 1H), 5.03-5.20 (m, 1H), 6.59-6.64 (m, 1H), 6.86 (s, 1H), 6.95-7.11(m, 1H), 7.21-7.33 (m, 1H), 7.58 (s, 2H), 7.78 (s, 1H), 8.14 (s, 1H). MS(ESI, pos. ion) m/z 453 [M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3-chlorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-178)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.59-0.75 (m, 1H), 0.76-0.99 (m, 2H),0.99-1.14 (m, 4H), 1.14-1.41 (m, 1H), 1.80-1.99 (m, 1H), 2.02-2.31 (m,2H), 2.58-2.69 (m, 1H), 3.48-3.71 (m, 1H), 3.77-3.98 (m, 1H), 3.98-4.07(m, 1H), 4.58-4.71 (m, 1H), 4.82-4.90 (m, 1H), 5.00-5.22 (m, 1H),6.55-6.67 (m, 1H), 6.67-6.80 (m, 1H), 6.80-6.97 (m, 1H), 7.13-7.22 (m,1H), 7.23-7.39 (m, 1H), 7.42-7.49 (m, 1H), 7.53-7.62 (m, 1H), 7.62-7.80(m, 1H), 7.85-8.08 (m, 1H). MS (ESI, pos. ion) m/z 463 [M+H]⁺.

(S)-(5-(3-chlorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-179)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.69-0.84 (m, 1H), 0.90-1.09 (m, 2H),1.10-1.26 (m, 4H), 1.37-1.52 (m, 1H), 1.80-1.95 (m, 2H), 1.98-2.11 (m,3H), 2.18-2.39 (m, 1H), 2.39-2.43 (m, 1H), 2.68-2.84 (m, 3H), 3.17-3.22(m, 2H), 4.14-4.34 (m, 1H), 4.70-4.89 (m, 1H), 6.62-6.78 (m, 1H),6.80-6.85 (m, 1H), 6.93-7.07 (m, 1H), 7.14-7.30 (m, 1H), 7.34-7.46 (m,1H), 7.55-7.66 (m, 1H), 7.79 (s, 1H), 8.00 (s, 1H). MS (ESI, pos. ion)m/z 491 [M+H]⁺.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3,5-difluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-180)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.16 (d, J=6.30 Hz, 3H), 1.55-1.69 (m,1H), 2.06-2.18 (m, 1H), 2.41-2.55 (m, 1H), 2.62-2.75 (m, 1H), 3.82 (s,3H), 3.90-4.01 (m, 2H), 4.01-4.15 (m, 1H), 4.64-4.75 (m, 1H), 5.21-5.31(m, 1H), 6.39 (d, J=8.40 Hz, 2H), 6.54-6.63 (m, 1H), 7.55-7.65 (m, 2H),7.86 (s, 1H), 8.04 (s, 1H). MS (ESI, pos. ion) m/z 455 [M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3,5-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-181)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.78-0.81 (m, 1H), 0.95-1.00 (m, 2H),1.13-1.20 (m, 4H), 1.40-1.53 (m, 1H), 2.01-2.08 (m, 1H), 2.22-2.27 (m,1H), 2.29-2.38 (m, 1H), 2.69-2.74 (m, 1H), 3.85-3.94 (m, 2H), 4.04-4.08(m, 2H), 4.75-4.84 (m, 1H), 5.22-5.28 (m, 1H), 6.41-6.48 (m, 2H),6.53-6.63 (m, 1H), 7.44 (d, J=8.40 Hz, 1H), 7.63 (d, J=8.40 Hz, 1H),7.88 (s, 1H), 8.07 (s, 1H). MS (ESI, pos. ion) m/z 465 [M+H]⁺.

(S)-methyl5-(3,5-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-182)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (m, 3H), 1.56-1.67 (m, 1H), 185-1.97(m, 2H), 2.01-2.11 (m, 2H), 2.11-2.18 (m, 1H), 2.43-2.52 (m, 1H),2.62-2.69 (m, 1H), 2.71-2.82 (m, 2H), 3.14-3.12 (m, 2H), 3.83 (s, 3H),4.22-4.33 (m, 1H), 4.75-4.84 (m, 1H), 6.41-6.48 (m, 2H), 6.53-6.63 (m,1H), 7.54-7.57 (m, 1H), 7.63-7.65 (m, 1H), 7.77 (s, 1H), 7.96 (s, 1H).MS (ESI, pos. ion) m/z 483 [M+H]⁺.

(S)-cyclopropyl(5-(3,5-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-183)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.76-7.84 (m, 1H), 0.91-1.03 (m, 2H),1.11-1.21 (m, 4H), 1.41-1.52 (m, 1H), 1.87-2.11 (m, 5H), 2.22-2.41 (m,2H), 3.20-3.28 (m, 2H), 6.39-6.46 (m, 2H), 6.53-6.63 (m, 1H), 7.43 (d,J=8.40 Hz, 1H), 7.63 (d, J=8.70 Hz, 1H), 7.80 (s, 1H), 8.00 (s, 1H). MS(ESI, pos. ion) m/z 493 [M+H]⁺.

(S)-(6-(5-amino-1,3,4-thiadiazol-2-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-184)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.79-0.88 (m, 1H), 0.92-1.09 (m, 2H),1.11-1.25 (m, 4H), 1.38-1.49 (m, 1H), 1.96-2.08 (m, 1H), 2.14-2.24 (m,1H), 2.24-2.35 (m, 1H), 2.62-2.73 (m, 1H), 4.73-4.82 (m, 1H), 6.75-6.89(m, 2H), 6.97-7.12 (m, 1H), 7.20-7.37 (m, 2H), 7.42-7.53 (m, 1H),8.08-8.19 (m, 1H). MS (ESI, pos. ion) m/z 407 [M+H]⁺.

(2S)-methyl5-(4-fluorophenoxy)-2-methyl-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-185)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.15 (d, J=6.40 Hz, 3H), 1.48-1.52 (m,1H), 2.01-2.11 (m, 2H), 2.20-2.30 (m, 1H), 2.38-2.45 (m, 1H), 2.55-2.70(m, 1H), 2.90-3.01 (m, 1H), 3.02-3.25 (m, 3H), 3.82 (s, 3H), 4.60-4.70(m, 1H), 4.80-4.95 (m, 1H), 6.68-6.75 (m, 2H), 6.91-7.00 (m, 2H),7.50-7.58 (m, 2H), 7.78 (s, 1H), 7.92 (s, 1H). MS (ESI, pos. ion) m/z451 [M+H]⁺.

(2S)-methyl5-(4-fluorophenoxy)-2-methyl-6-(1-(octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-186)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.14 (d, J=6.60 Hz, 3H), 1.48-1.62 (m,1H), 1.79-1.90 (m, 2H), 1.98-2.10 (m, 1H), 2.15-2.25 (m, 2H), 2.35-2.45(m, 1H), 2.58-2.70 (m, 5H), 2.95-3.05 (m, 2H), 3.80 (s, 3H), 4.58-4.80(m, 2H), 6.68-6.72 (m, 2H), 6.93-7.02 (m, 2H), 7.50-7.60 (m, 2H), 7.76(s, 1H), 7.89 (s, 1H). MS (ESI, pos. ion) m/z 491 [M+H]⁺.

(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-187)

For(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone,1-benzyl-4-bromo-1H-1,2,3-triazole was used as the aryl bromide source.The benzyl group was removed using the hydrogenation conditions outlinedabove for Intermediate 1, Step 2. ¹H NMR (400 MHz, CD₃OD) δ ppm0.75-0.87 (m, 1H), 0.91-1.03 (m, 2H), 1.11-1.22 (m, 4H), 1.39-1.52 (m,1H), 1.95-2.08 (m, 1H), 2.17-2.29 (m, 1H), 2.29-2.38 (m, 1H), 2.66-2.82(m, 1H), 4.73-4.88 (m, 1H), 6.71-6.89 (m, 2H), 6.96-7.22 (m, 1H),7.21-7.38 (m, 2H), 7.44-7.53 (m, 1H), 8.03 (s, 1H), 8.03-8.14 (m, 1H).MS (ESI, pos. ion) m/z 375 [M+H]⁺.

Methyl(S)-5-(3-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-188)

MS (ESI, pos. ion) m/z 465 [M+H]⁺.

Methyl(S)-5-(3-chlorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-189)

MS (ESI, pos. ion) m/z 481 [M+H]⁺.

(S)-1-(5-(4-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-190)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.10-1.15 (m, 3H), 1.30-1.43 (m, 1H),1.76-1.86 (m, 2H), 1.94-2.10 (m, 2H), 2.20-2.35 (m, 5H), 2.63-2.76 (m,3H), 3.06-3.18 (m, 2H), 4.15-4.26 (m, 1H), 4.69-4.81 (m, 1H), 6.70-6.78(m, 2H), 6.97-7.03 (m, 2H), 7.30 (br s, 1H), 7.61 (d, J=8.40 Hz, 1H),7.78 (s, 1H), 7.95 (s, 1H). MS (ESI, pos. ion) m/z 449 [M+H]⁺.

(S)-1-(5-(4-chlorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-191)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.13 (d, J=6.30 Hz, 3H), 1.35-1.51 (m,1H), 1.75-1.90 (m, 2H), 1.95-2.10 (m, 2H), 2.15-2.33 (m, 5H), 2.63-2.77(m, 3H), 3.08-3.15 (m, 2H), 4.15-4.27 (m, 1H), 4.68-4.81 (m, 1H),6.73-6.80 (m, 2H), 7.20-7.39 (m, 3H), 7.59-7.63 (m, 1H), 7.78 (s, 1H),7.95 (s, 1H). MS (ESI, pos. ion) m/z 465 [M+H]⁺.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-192)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.04 (d, J=6.80 Hz, 3H), 1.41-1.48 (m,1H), 1.93-2.02 (m, 1H), 2.29-2.36 (m, 1H), 2.51-2.57 (m, 1H), 3.70 (s,3H), 3.77-3.82 (m, 2H), 3.93-3.99 (m, 2H), 4.50-4.60 (m, 1H), 5.08-5.16(m, 1H), 6.40-6.45 (m, 1H), 6.55-6.64 (m, 1H), 6.95-7.07 (m, 1H),7.40-7.51 (m, 2H), 7.74 (s, 1H), 7.91 (s, 1H). MS (ESI, pos. ion) m/z455 [M+H]⁺.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-2-methyl-5-phenoxy-3,4-dihydroquinoline-1(2H)-carboxylate(I-193)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.03 (d, J=6.80 Hz, 3H), 1.38-1.48 (m,1H), 1.91-2.01 (m, 1H), 2.35-2.48 (m, 1H), 2.49-2.58 (m, 1H), 3.70 (s,3H), 3.73-3.82 (m, 2H), 2.85-2.95 (m, 2H), 4.43-4.53 (m, 1H), 5.05-5.13(m, 1H), 6.65 (d, J=8.80 Hz, 2H), 6.84-6.89 (m, 1H), 7.12-7.18 (m, 2H),7.47 (s, 1H), 7.91 (s, 1H), 7.74 (s, 1H). MS (ESI, pos. ion) m/z 419[M+H]⁺.

(S)-cyclopropyl(5-(2-methoxyphenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-194)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.81 (m, 1H), 0.92-1.02 (m, 2H),1.14-1.22 (m, 4H), 1.39-1.49 (m, 1H), 1.77-1.88 (m, 2H), 2.01-2.09 (m,3H), 2.21-2.35 (m, 2H), 2.69-2.79 (m, 3H), 3.14-3.19 (m, 2H), 4.02 (s,3H), 4.15-4.25 (m, 1H), 4.75-4.84 (m, 1H), 6.30 (d, J=3.60 Hz, 1H),6.69-6.73 (m, 1H), 6.94-6.98 (m, 1H), 7.11-7.15 (m, 1H), 7.38 (d, J=6.30Hz, 1H), 7.65 (d, J=6.30 Hz, 1H), 7.86 (s, 1H), 8.05 (s, 1H). MS (ESI,pos. ion) m/z 487 [M+H]⁺.

(S)-cyclopropyl(5-(3-methoxyphenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-195)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.78-0.85 (m, 1H), 0.83-1.01 (m, 2H),1.12-1.21 (m, 4H), 1.38-1.46 (m, 1H), 1.85-1.95 (m, 2H), 1.97-2.09 (m,3H), 2.20-2.47 (m, 2H), 2.69-2.81 (m, 3H), 3.15-3.20 (m, 2H), 3.74 (s,3H), 4.21-4.31 (m, 1H), 4.75-4.85 (m, 1H), 6.33-6.38 (m, 2H), 6.55-6.58(m, 1H), 7.15-7.19 (m, 1H), 7.37-7.41 (m, 1H), 7.64-7.68 (m, 1H), 7.81(s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 487 [M+H]⁺.

(S)-cyclopropyl(5-(4-methoxyphenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-196)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.63-0.71 (m, 1H), 0.83-0.91 (m, 2H),0.96-1.11 (m, 4H), 1.25-1.31 (m, 1H), 1.66-1.78 (m, 2H), 1.85-1.95 (m,3H), 2.10-2.21 (m, 2H), 2.57-2.69 (m, 3H), 3.02-3.08 (m, 2H), 3.61 (s,3H), 4.09-4.19 (m, 1H), 4.63-4.69 (m, 1H), 6.57-6.61 (m, 2H), 6.70-6.73(m, 2H), 7.24 (d, J=8.40 Hz, 1H), 7.51 (d, J=8.40 Hz, 1H), 7.69 (s, 1H),7.81 (s, 1H). MS (ESI, pos. ion) m/z 487 [M+H]⁺.

(S)-methyl5-(2-methoxyphenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-197)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.04 (d, J=6.40 Hz, 3H), 1.42-1.49 (m,1H), 1.69-1.78 (m, 2H), 1.90-1.99 (m, 3H), 2.31-2.39 (m, 1H), 2.52-2.59(m, 1H), 2.61-2.68 (m, 2H), 3.05-3.11 (m, 2H), 3.70 (s, 3H), 3.89 (s,3H), 4.05-4.15 (m, 1H), 4.46-4.58 (m, 1H), 6.15-6.17 (m, 1H), 6.52-6.58(m, 1H), 6.75-6.81 (m, 1H), 6.96-9.99 (m, 1H), 7.44 (s, 1H), 7.71 (s,1H), 7.90 (s, 1H). MS (ESI, pos. ion) m/z 477 [M+H]⁺.

(S)-methyl5-(3-methoxyphenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-198)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.15 (d, J=6.40 Hz, 3H), 1.42-1.49 (m,1H), 1.78-1.91 (m, 2H), 2.01-2.13 (m, 3H), 2.41-2.48 (m, 1H), 7.26-2.78(m, 3H), 3.12-3.20 (m, 2H), 3.72 (s, 3H), 3.82 (s, 3H), 4.18-4.28 (m,1H), 4.63-4.72 (m, 1H), 6.29-6.36 (m, 1H), 6.53-6.58 (m, 1H), 7.10-7.17(m, 1H), 7.55 (s, 1H), 7.77 (s, 1H), 7.91 (s, 1H). MS (ESI, pos. ion)m/z 477 [M+H]⁺.

(S)-methyl5-(4-methoxyphenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-199)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.15 (d, J=6.40 Hz, 3H), 1.42-1.49 (m,1H), 1.80-1.91 (m, 2H), 2.01-2.13 (m, 3H), 2.41-2.48 (m, 1H), 2.63-2.79(m, 3H), 3.12-3.20 (m, 2H), 3.72 (s, 3H), 3.81 (s, 3H), 4.18-4.28 (m,1H), 4.63-4.69 (m, 1H), 6.68-6.70 (m, 2H), 6.80-6.80 (m, 2H), 7.53 (s,2H), 7.53 (s, 1H), 7.95 (s, 1H). MS (ESI, pos. ion) m/z 477 [M+H]⁺.

(S)-methyl2-methyl-5-phenoxy-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-200)

¹H NMR (300 MHz, CDCl₃) δ ppm 1.10-1.15 (m, 3H), 1.48-1.59 (m, 1H),1.75-1.95 (m, 2H), 1.96-2.12 (m, 3H), 2.40-2.50 (m, 1H), 2.56-2.81 (m,3H), 3.16-3.37 (m, 2H), 3.81 (s, 3H), 4.08-4.20 (m, 1H), 4.61-4.72 (m,1H), 6.71-6.79 (m, 2H), 6.89-6.95 (m, 1H), 7.21-7.26 (m, 2H), 7.45-7.48(m, 1H), 7.63-7.68 (m, 2H), 7.72 (s, 1H). MS (ESI, pos. ion) m/z 447[M+H]⁺.

(S)-1-(2-methyl-5-phenoxy-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-201)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.14 (d, J=6.60 Hz, 3H), 1.30-1.43 (m,1H), 1.76-1.90 (m, 2H), 1.97-2.11 (m, 2H), 2.21-2.32 ((m, 5H), 2.65-2.80(m, 3H), 3.10-3.21 (m, 2H), 4.15-4.29 (m, 1H), 4.71-4.84 (m, 1H),6.75-6.81 (m, 2H), 6.98 (d, J=7.20 Hz, 1H), 7.25-7.34 (m, 3H), 7.62 (d,J=6.60 Hz, 1H), 7.80 (s, 1H), 7.95 (s, 1H). MS (ESI, pos. ion) m/z 431[M+H]⁺.

(S)-3-(1-(cyclopropanecarbonyl)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(I-202)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.76-0.83 (m, 1H), 1.13-1.22 (m, 4H),1.29-1.38 (m, 1H), 1.81-1.94 (m, 2H), 1.96-2.10 (m, 3H), 2.22-2.38 (m,2H), 2.36-2.78 (m, 3H), 3.15-3.21 (m, 2H), 4.24-4.31 (m, 1H), 4.80-4.85(m, 1H), 7.78 (s, 1H), 7.89 (s, 1H). MS (ESI, pos. ion) m/z 482 [M+H]⁺.

(S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(pyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-203)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.11 (d, J=6.60 Hz, 3H), 1.29-1.49 (m,1H), 1.75-1.90 (m, 2H), 1.92-2.01 (m, 2H), 2.18 (s, 5H), 2.59-2.69 (m,1H), 2.70-2.80 (m, 2H), 4.15-4.26 (m, 1H), 4.68-4.81 (m, 1H), 6.85-6.91(m, 1H), 6.95-7.04 (m, 1H), 7.21-7.33 (m, 1H), 7.55-7.58 (m, 1H),7.71-7.79 (m, 2H), 7.89 (s, 1H), 7.97-8.04 (m, 1H). MS (ESI, pos. ion)m/z 432 [M+H]⁺.

(S)-cyclopropyl(8-fluoro-2-methyl-5-phenoxy-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-204)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.63-0.95 (m, 4H), 1.04-1.31 (m, 4H),1.60-1.71 (m, 3H), 1.82-1.91 (m, 2H), 2.11-2.23 (m, 2H), 2.54-2.57 (m,2H), 2.95-3.05 (m, 1H), 3.27-3.40 (m, 1H), 4.60-4.71 (m, 1H), 6.81 (d,J=8.00 Hz, 2H), 6.95-7.01 (m, 1H), 7.25-7.32 (m, 2H), 7.64-7.70 (m, 1H),7.80 (s, 1H), 8.10 (s, 1H). MS (ESI, pos. ion) m/z 475 [M+H]⁺.

(S)-methyl8-fluoro-2-methyl-5-phenoxy-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-205)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.18 (d, J=6.40 Hz, 3H), 1.35-1.46 (m 1H),1.76-1.84 (m, 2H), 1.96-2.05 (m, 2H), 2.20-2.32 (m, 2H), 2.68-2.73 (m,3H), 3.15-3.20 (m, 2H), 3.79 (s, 3H), 4.17-4.22 (m, 1H), 4.43-4.53 (m,1H), 6.75-6.78 (m, 2H), 6.95-7.00 (m, 1H), 7.25-7.31 (m, 2H), 7.45-7.52(m, 1H), 7.79 (s, 1H), 7.97 (s, 1H). MS (ESI, pos. ion) m/z 465 [M+H]⁺.

(S)-1-(8-fluoro-2-methyl-5-phenoxy-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-206)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.10-1.25 (m, 4H), 1.78-1.91 (m, 2H),1.96-2.07 (m, 2H), 2.10-2.20 (m, 3H), 2.25-2.37 (m, 2H), 2.67-2.79 (m,3H), 3.10-3.18 (m, 2H), 4.18-4.18 (m 1H), 4.77-4.83 (m, 1H), 6.79-6.82(m, 2H), 6.95-7.03 (m, 1H), 7.25-7.30 (m, 2H), 7.55-7.59 (m, 1H), 7.83(s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 449 [M+H]⁺.

(S)-cyclopropyl(8-fluoro-5-(3-methoxyphenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-207)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.61-0.85 (m, 4H), 1.02-1.11 (m, 4H), 1.60(m, 1H), 2.04-2.20 (m, 6H), 2.62-2.66 (m, 1H), 3.03-3.10 (m, 2H),3.39-3.42 (m, 2H), 3.63 (s, 3H), 4.37-4.42 (m, 1H), 4.60-4.67 (m, 1H),6.23-6.28 (m, 2H), 6.46-6.48 (m, 1H), 7.03-7.08 (m, 1H), 7.40-7.42 (m,1H), 7.78 (s, 1H), 7.90 (s, 1H). MS (ESI, pos. ion) m/z 505 [M+H]⁺.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3-chloro-4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-208)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.99 (d, J=6.45 Hz, 3H), 1.33-1.56 (m,2H), 1.80-2.02 (m, 2H), 2.22-2.40 (m, 2H), 3.34-3.48 (m, 1H), 3.55-3.64(m, 1H), 3.65 (s, 3H), 3.69-3.84 (m, 1H), 4.36-4.61 (m, 1H), 4.70-4.93(m, 1H), 6.52-6.70 (m, 1H), 6.87-7.04 (m, 1H), 7.12-7.31 (m, 1H), 7.52(s, 2H), 7.69-7.79 (m, 1H), 8.06 (br d, J=13.49 Hz, 1H). MS (ESI, pos.ion) m/z 471 [M+H]⁺.

Example 39(S)-4-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide(I-209)

Step 1.(S)-4-(1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide

A 100-mL, round-bottom flask equipped with a balloon filled with air wascharged with(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.300 g, 1.06 mmol), 4-carbamoylphenylboronic acid (0.437 g, 2.65mmol), pyridine (1 mL), dichloromethane (40 mL), copper (II) acetate(0.580 g, 3.20 mmol) and 4 Å molecular sieves (4.0 g). The resultingmixture stirred for 3 days at room temperature. The reaction mixture wasfiltered, and the filtrate was concentrated under vacuum. The residuewas purified by preparative thin layer chromatography (eluting with 3:1,ethyl acetate/petroleum ether) to afford(S)-4-(1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide(0.148 g, 35%) as yellow oil. MS (ESI, pos. ion) m/z 403, 405 [M+H]⁺.

Step 2.(S)-4-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide

A 50-mL, round-bottom flask was charged with(S)-4-(1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide(0.068 g, 0.17 mmol),1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.059 g, 0.25 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.014 g, 0.02 mmol), potassium carbonate (0.070 g,0.50 mmol), 1,4-dioxane (20 mL) and water (2 mL). The resulting mixturestirred overnight at 100° C. After cooling to room temperature, thereaction mixture was passed through a short pad of celite, and thefiltrate was concentrated under vacuum. The residue was purified bypreparative thin layer chromatography (eluting with 1:1, ethylacetate/petroleum ether). The product was further purified bypreparative-HPLC with the following conditions (Waters I): Column,XBridge Prep C18 OBD Column, 19×150 mm 5 um 13 nm; mobile phase, water(0.05% ammonium bicarbonate) and acetonitrile (15.0% to 95% acetonitrilein 12 min; flow rate: 20 mL/min); Detector, UV 254/220 nm. This afforded(S)-4-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide(0.029 g, 40%) as an off-white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm0.93-1.03 (m, 4H), 1.15 (d, J=6.60 Hz, 3H, 1.19-1.42 (m, 1H), 2.18-2.27(m, 5H), 2.67-2.75 (m, 1H), 3.56-3.63 (m, 1H), 4.77-4.79 (m, 1H),6.85-6.88 (m, 2H), 7.37 (m, 1H), 7.63 (d, J=8.40 Hz, 1H), 7.77 (s, 1H),7.81-7.85 (m, 2H), 7.94 (s, 1H). MS (ESI, pos. ion) m/z 431 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 39:

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-210)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.95-1.02 (m, 4H), 1.16 (d, J=6.60 Hz,3H), 1.30-1.48 (m, 1H), 2.15-2.40 (m, 5H), 2.65-2.80 (m, 1H), 3.55-3.65(m, 1H), 4.70-4.89 (m, 1H), 6.35-6.45 (m, 1H), 6.95-7.00 (m, 2H),7.15-7.25 (m, 1H), 7.29-7.38 (m, 1H), 7.61 (d, J=8.40 Hz, 1H), 7.79 (s,1H), 7.97 (s, 1H). MS (ESI, pos. ion) m/z 406 [M+H]⁺.

(S)-1-(5-(2-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-211)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.89-1.01 (m, 4H), 1.15 (d, J=6.80 Hz,3H), 1.30-1.45 (m, 1H), 2.05-2.34 (m, 5H), 2.55-2.78 (m, 1H), 3.55-3.65(m, 1H), 4.68-4.88 (m, 1H), 6.31-6.38 (m, 1H), 6.97 (t, J=7.20 Hz, 1H),7.07 (t, J=7.20 Hz, 1H), 7.25-7.40 (m, 1H), 7.45-7.50 (m, 1H), 7.58-7.65(m, 1H), 7.81 (s, 1H), 7.98 (s, 1H). MS (ESI, pos. ion) m/z 422 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-212)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.95-1.01 (m, 4H), 1.13 (d, J=6.80 Hz,3H), 1.51-1.65 (m, 1H), 2.01-2.10 (m, 1H), 2.35-2.45 (m, 1H), 2.58-2.71(m, 1H), 3.55-3.60 (m, 1H), 3.81 (s, 3H), 4.58-4.62 (m, 1H), 6.69-6.75(m, 2H), 6.91-7.01 (m, 2H), 7.49-7.59 (m, 2H), 7.74 (s, 1H), 7.89 (s,1H). MS (ESI, pos. ion) m/z 422 [M+H]⁺.

Example 13-5 (S)-methyl5-(4-cyanophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-213)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.97-1.01 (m, 4H), 1.15 (d, J=6.60 Hz,3H), 1.55-1.65 (m, 1H), 1.98-2.15 (m, 1H), 2.35-2.45 (m, 1H), 2.55-2.68(m, 1H), 3.50-3.60 (m, 1H), 3.83 (s, 3H), 4.61-4.72 (m, 1H), 6.90-6.98(m, 2H), 7.51-7.71 (m, 5H), 7.89 (s, 1H). MS (ESI, pos. ion) m/z 429[M+H]⁺.

(S)-methyl5-(4-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-214)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.97-1.01 (m, 4H), 1.16 (d, J=6.60 Hz,3H), 1.50-1.68 (m, 1H), 1.99-2.15 (m, 1H), 2.35-2.48 (m, 1H), 2.55-2.75(m, 1H), 3.52-3.62 (m, 1H), 3.82 (s, 3H), 4.58-4.70 (m, 1H), 6.75-6.81(m, 2H), 7.20-7.28 (m, 2H), 7.48-7.60 (m, 2H), 7.73 (s, 1H), 7.89 (s,1H). MS (ESI, pos. ion) m/z 438 [M+H]⁺.

(S)-methyl5-(2-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-215)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.90-1.01 (m, 4H), 1.15 (d, J=6.60 Hz,3H), 1.52-1.65 (m, 1H), 1.99-2.10 (m, 1H), 2.10-2.90 (br m, 2H),3.50-3.60 (m, 1H), 3.81 (s, 3H), 4.61-4.71 (m, 1H), 6.29-6.38 (m, 1H),6.85-6.95 (m, 1H), 6.98-7.05 (m, 1H), 7.45-7.62 (m, 3H), 7.76 (s, 1H),7.92 (s, 1H). MS (ESI, pos. ion) m/z 438 [M+H]⁺.

(S)-methyl5-(4-carbamoylphenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-216)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.89-1.05 (m, 4H), 1.16 (d, J=6.60 Hz,3H), 1.55-1.65 (m, 1H), 1.98-2.15 (m, 1H), 2.38-2.48 (m, 1H), 2.55-2.75(m, 1H), 3.50-3.60 (m, 1H), 3.83 (s, 3H), 4.60-4.75 (m, 1H), 6.85 (d,J=8.70 Hz, 2H), 7.50-7.62 (m, 2H), 7.70-7.92 (m, 4H). MS (ESI, pos. ion)m/z 447 [M+H]⁺.

(S)-4-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile(I-217)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.93-0.99 (m, 4H), 1.12 (d, J=6.60 Hz,3H), 1.30-1.45 (m, 1H), 2.10-2.30 (m, 5H), 2.55-2.70 (m, 1H), 3.50-3.60(m, 1H), 4.65-4.83 (m, 1H), 6.93 (d, J=9.00 Hz, 2H), 7.28-7.35 (m, 1H),7.55-7.68 (m, 3H), 7.71 (s, 1H), 7.90 (s, 1H). MS (ESI, pos. ion) m/z413 [M+H]⁺.

(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-5-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-218)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.72-0.87 (m, 1H), 0.95-1.08 (m, 2H),1.11-1.22 (m, 4H), 1.35-1.51 (m, 1H), 1.95-2.08 (m, 1H), 2.18-2.28 (m,1H), 2.29-2.39 (m, 1H), 2.69-2.79 (m, 1H), 4.72-4.84 (m, 1H), 6.51-6.69(m, 2H), 6.71-6.82 (m, 2H), 6.89-7.02 (m, 1H), 7.12-7.37 (m, 2H),7.39-8.00 (m, 3H). MS (ESI, pos. ion) m/z 374 [M+H]⁺.

(S)-cyclopropyl(2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(I-219)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.63-99 (m, 3H), 1.03 (d, J=9.90 Hz, 4H),1.30-1.50 (m, 1H), 1.88-2.01 (m, 1H), 2.01-2.18 (m, 1H), 2.20-2.39 (m,1H), 2.53-2.62 (m, 1H), 4.00 (s, 3H), 4.58-4.79 (m, 1H), 6.74-6.89 (m,2H), 6.90-7.09 (m, 1H), 7.19-7.37 (m, 2H), 7.42-7.54 (m, 1H), 8.03-8.15(m, 2H). MS (ESI, pos. ion) m/z 389 [M+H]⁺.

(S)-cyclopropyl(2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(I-220)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.72-0.89 (m, 1H), 0.92-1.09 (m, 2H),1.11-1.29 (m, 4H), 1.35-1.52 (m, 1H), 1.88-2.07 (m, 1H), 2.08-2.27 (m,1H), 2.27-2.46 (m, 1H), 2.62-2.81 (m, 4H), 4.74-4.83 (m, 1H), 6.71-6.98(m, 2H), 6.89-7.19 (m, 1H), 7.28-7.39 (m, 2H), 7.39-7.69 (m, 1H),8.21-8.39 (m, 1H). MS (ESI, pos. ion) m/z 406 [M+H]⁺.

(S)-cyclopropyl(2-methyl-6-(1-methyl-1H-imidazol-4-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(I-221)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.72-0.84 (m, 1H), 0.91-1.03 (m, 2H),1.08-1.19 (m, 4H), 1.29-1.44 (m, 1H), 1.88-2.07 (m, 1H), 2.13-2.33 (m,2H), 2.62-2.76 (m, 1H), 3.64 (s, 3H), 4.76-4.83 (m, 1H), 6.74-6.79 (m,2H), 6.86-7.06 (m, 1H), 7.20-7.37 (m, 3H), 7.38-7.47 (m, 1H), 7.61 (s,1H), 7.76-8.02 (m, 1H). MS (ESI, pos. ion) m/z 388 [M+H]⁺.

Methyl(2S)-6-(1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-222)

MS (ESI, pos. ion) m/z 514 [M+H]⁺.

methyl(S)-6-(1-(1,1-dioxidothietan-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-223)

MS (ESI, pos. ion) m/z 486 [M+H]⁺.

(S)-cyclopropyl(2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(I-224)

¹H NMR (400 MHz, CDCl₃) δ ppm 0.75-0.88 (m, 1H), 0.93-1.04 (m, 2H),1.11-1.23 (m, 4H), 1.38-1.52 (m, 1H), 1.95-2.08 (m, 1H), 2.17-2.29 (m,1H), 2.29-2.38 (m, 1H), 2.66-2.81 (m, 1H), 4.72-4.86 (m, 1H), 6.69-6.89(m, 2H), 6.96-7.12 (m, 1H), 7.22-7.37 (m, 2H), 7.45-7.54 (m, 1H), 8.03(s, 1H), 8.00-8.14 (m, 1H). MS (ESI, pos. ion) m/z 388 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-225)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.00-1.03 (m, 4H), 1.14 (d, J=6.30 Hz,3H), 1.36-1.38 (m, 1H), 2.19-2.24 (m, 5H), 2.66-2.76 (m, 1H), 3.57-3.64(m, 1H), 4.77 (m, 1H), 6.75-6.81 (m, 2H), 6.97-7.04 (m, 2H), 7.32 (m,1H), 7.61 (d, J=8.40 Hz, 1H), 7.75 (s, 1H), 7.91 (s, 1H). MS (ESI, pos.ion) m/z 406 [M+H]⁺.

(S)-1-(5-(4-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-226)

¹H NMR (300 MHz, CD₃OD) δ 0.89-0.94 (m, 4H), 1.15 (d, J=6.60 Hz, 3H),1.34-1.44 (m, 1H), 2.26-2.34 (m, 5H), 2.60-2.65 (m, 1H), 4.70 (m, 1H),6.75 (d, J=8.40 Hz, 2H), 7.35 (m, 1H), 7.60 (d, J=8.40 Hz, 1H), 7.75 (s,1H), 7.91 (s, 1H). MS (ESI, pos. ion) m/z 422 [M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-227)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.73-0.82 (m, 1H), 0.90-1.01 (m, 2H),1.11-1.21 (m, 4H), 1.25-1.31 (m, 1H), 1.31-1.44 (m, 1H), 1.93-2.09 (m,1H), 2.13-2.45 (m, 2H), 2.68-2.77 (m, 1H), 4.73-4.81 (m, 1H), 6.79 (d,J=7.80 Hz, 2H), 6.95-7.02 (m, 1H), 7.28-7.33 (m, 2H), 7.39 (d, J=8.40Hz, 1H), 7.66 (d, J=8.40 Hz, 1H), 7.91 (s, 2H). MS (ESI, pos. ion) m/z374[M+H]⁺.

3-[4-[(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]-1λ⁶-thietane-1,1-dione(I-229)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.92-1.01 (m, 2H), 1.12-1.23 (m, 4H),1.37-1.46 (m, 1H), 1.96-2.05 (m, 1H), 2.11-2.36 (m, 2H), 2.65-2.78 (m,1H), 4.56-4.79 (m, 4H), 4.73-4.83 (m, 1H), 5.22-5.34 (m, 1H), 6.75-6.81(m, 2H), 6.95-7.06 (m, 2H), 7.40 (d, J=8.40 Hz, 1H), 7.63 (d, J=8.80 Hz,1H), 7.92 (s, 1H), 8.12 (s, 1H). MS (ESI, pos. ion) m/z 524[M+H]⁺.

3-[4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]-1λ⁶-thietane-1,1-dione(I-230)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.64-0.81 (m, 1H), 0.89-1.02 (m, 2H),1.12-1.22 (m, 4H), 1.33-1.45 (m, 1H), 1.92-2.05 (m, 1H), 2.15-4.41 (m,2H), 2.63-2.77 (m, 1H), 4.54-4.63 (m, 4H), 4.75-4.79 (m, 1H), 5.25-5.34(m, 1H), 6.79 (d, J=7.80 Hz, 2H), 6.95-7.04 (m, 1H), 7.25-7.29 (m, 2H),7.35-7.42 (m, 1H), 7.63 (d, J=8.40 Hz, 1H), 7.90 (s, 1H), 8.11 (s, 1H).MS (ESI, pos. ion) m/z 478[M+H]⁺.

(S)-cyclopropyl(6-(isoxazol-4-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(I-231)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.82 (m, 1H), 0.85-1.14 (m, 2H),1.11-1.25 (m, 4H), 1.40-1.49 (m, 1H), 1.95-2.08 (m, 1H), 2.15-2.34 (m,2H), 2.67-2.76 (m, 1H), 4.77-4.85 (m, 1H), 6.78-6.81 (m, 2H), 6.99-7.04(m, 1H), 7.25-7.35 (m, 2H), 7.45-7.53 (m, 1H), 7.66-7.71 (m, 1H), 8.78(s, 1H), 8.88 (s, 1H). MS (ESI, pos. ion) m/z 375[M+H]⁺.

(S)-methyl2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-3,4-dihydroquinoline-1(2H)-carboxylate(I-232)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.04 (d, J=6.40 Hz, 3H), 1.39-1.43 (m,1H), 1.81-2.02 (m, 1H), 2.25-2.42 (m, 1H), 2.45-2.62 (m, 1H), 3.71 (s,1H), 3.92 (s, 2H), 4.42-4.65 (m, 1H), 6.68 (d, J=8.00 Hz, 2H), 6.88 (t,J=7.20 Hz, 1H), 7.16-7.13 (m, 2H), 7.55 (d, J=8.80 Hz, 1H), 7.88 (t,J=6.40 Hz, 2H). MS (ESI, pos. ion) m/z 379[M+H]⁺.

(S)-1-(2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-233)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.16 (d, J=6.60 Hz, 3H), 1.30-1.40 (m,1H), 2.15-2.26 (m, 5H), 2.64-2.74 (m, 1H), 4.04 (s, 3H), 4.76-4.80 (m,1H), 6.80-6.83 (m, 2H), 6.99-7.02 (m, 1H), 7.24-7.30 (m, 2H), 7.41-7.43(m, 1H), 8.01 (s, 1H), 8.08 (d, J=8.40 Hz, 1H). MS (ESI, pos. ion) m/z363[M+H]⁺.

(S)-cyclopropyl(5-(3-methoxyphenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-234)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.70-0.80 (m, 1H), 0.89-1.02 (m, 2H),1.13-1.20 (m, 4H), 1.30-1.45 (m, 1H), 1.98-2.05 (m, 1H), 2.15-2.35 (m,2H), 2.70-2.75 (m, 1H), 3.75 (s, 3H), 4.06 (s, 3H), 4.79-4.83 (m, 1H),6.33-6.37 (m, 1H), 6.41-6.43 (m, 1H), 6.57-6.61 (m, 1H), 7.14-7.19 (m,1H), 7.48 (d, J=8.40 Hz, 1H), 8.00 (s, 1H), 8.07 (d, J=8.40 Hz, 1H). MS(ESI, pos. ion) m/z 419[M+H]⁺.

(S)-cyclopropyl(5-(3-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-235)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.83 (m, 1H), 0.89-1.05 (m, 2H),1.10-1.25 (m, 4H), 1.35-1.45 (m, 1H), 1.95-2.05 (m, 1H), 2.15-2.48 (m,2H), 2.65-2.75 (m, 1H), 4.06 (s, 3H), 4.75-4.85 (m, 1H), 6.55-6.67 (m,2H), 6.69-6.77 (m, 1H), 7.09-7.27 (m, 1H), 7.51 (d, J=8.70 Hz, 1H), 8.04(s, 1H), 8.07 (d, J=8.40 Hz, 1H). MS (ESI, pos. ion) m/z 407[M+H]⁺.

(S)-cyclopropyl(5-(4-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-236)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.72-0.82 (m, 1H), 0.87-1.02 (m, 2H),1.08-1.21 (m, 4H), 1.37-1.48 (m, 1H), 1.95-2.05 (m, 1H), 2.15-2.36 (m,2H), 2.65-2.78 (m, 1H), 4.71-4.85 (m, 1H), 6.75-6.83 (m, 2H), 6.95-7.05(m, 2H), 7.48 (d, J=8.40 Hz, 1H), 8.03 (s, 1H), 8.07 (d, J=8.70 Hz, 1H).MS (ESI, pos. ion) m/z 407[M+H]⁺.

(S)-cyclopropyl(6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(I-237)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.63-0.72 (m, 1H), 0.83-0.99 (m, 5H),1.04-1.31 (m, 4H), 1.60-1.71 (m, 3H), 2.11-2.33 (m, 2H), 2.68-2.77 (m,1H), 3.52-3.59 (m, 1H), 4.71-4.78 (m, 1H), 6.73-6.78 (m, 2H), 6.95-7.01(m, 1H), 7.25-7.32 (m, 2H), 7.45-7.55 (m, 1H), 7.75 (s, 1H), 7.92 (s,1H). MS (ESI, pos. ion) m/z 432[M+H]⁺.

(S)-cyclopropyl(8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-238)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.69-0.80 (m, 1H), 0.91-1.08 (m, 3H),1.10-1.36 (m, 4H), 1.70-1.80 (m, 1H), 2.11-2.33 (m, 2H), 2.71-2.79 (m,1H), 4.73-4.80 (m, 1H), 6.76-6.82 (m, 2H), 6.95-7.03 (m, 1H), 7.25-7.32(m, 2H), 7.51-7.62 (m, 1H), 7.93 (s, 1H). MS (ESI, pos. ion) m/z392[M+H]⁺.

(S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-3,4-dihydroquinoline-1(2H)-carboxylate(I-239)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.95-1.01 (m, 4H), 1.18 (d, J=6.40 Hz,3H), 1.35-1.46 (m 1H), 2.20-2.32 (m, 2H), 2.68-2.73 (m, 1H), 3.55-3.62(m, 1H), 3.79 (s, 3H), 4.43-4.53 (m, 1H), 6.75-6.78 (m, 2H), 6.95-7.02(m, 1H), 7.25-7.29 (m, 2H), 7.41-7.45 (m, 1H), 7.77 (s, 1H), 7.93 (s,1H). MS (ESI, pos. ion) m/z 422[M+H]⁺.

(S)-methyl8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-240)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.19 (d, J=6.40 Hz, 3H), 1.35-1.46 (m 1H),2.20-2.32 (m, 2H), 2.68-2.73 (m, 1H), 3.79 (s, 3H), 4.46-4.53 (m, 1H),6.77-6.79 (m, 2H), 6.95-7.02 (m, 1H), 7.25-7.29 (m, 2H), 7.42-7.45 (m,1H), 7.91 (br s, 2H). MS (ESI, pos. ion) m/z 382[M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-241)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.95-1.02 (m, 4H), 1.10-1.23 (m, 4H),2.16-2.15 (m, 3H), 2.24-2.37 (m, 2H), 2.68-2.80 (m, 1H), 3.55-3.64 (m,1H), 4.76-4.85 (m, 1H), 6.77-6.82 (m, 2H), 6.95-7.03 (m, 1H), 7.25-7.33(m, 2H), 7.49-7.54 (m, 1H), 7.81 (s, 1H), 7.98 (s, 1H). MS (ESI, pos.ion) m/z 406[M+H]⁺.

(S)-1-(8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-242)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.09-1.30 (m, 4H), 2.11-2.37 (m, 5H),2.71-2.81 (m, 1H), 4.75-4.85 (m, 1H), 6.81 (d, J=7.80 Hz, 2H), 7.00 (t,J=7.20 Hz, 1H), 7.29 (t, J=8.10 Hz, 2H), 7.57 (d, J=10.80 Hz, 2H), 7.95(s, 2H). MS (ESI, pos. ion) m/z 366[M+H]⁺.

(S)-cyclopropyl(6-cyclopropyl-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone (I-243)

¹H NMR (300 MHz, CDCl₃) δ ppm 0.57-0.72 (m, 3H), 0.79-0.91 (m, 3H),1.91-2.03 (m, 1H), 1.09 (d, J=6.60 Hz, 3H), 1.25-1.31 (m, 1H), 1.32-1.34(m, 1H), 1.84-1.91 (m, 2H), 2.13-2.21 (m, 1H), 2.25-2.37 (m, 1H),2.66-2.75 (m, 1H), 4.78-4.65 (m, 1H), 6.73-6.81 (m, 3H), 6.95-7.04 (m,1H), 7.19 (d, J=7.80 Hz, 1H), 7.26-7.33 (m, 2H). MS (ESI, pos. ion) m/z348[M+H]⁺.

(S)-methyl6-cyclopropyl-2-methyl-5-phenoxy-3,4-dihydroquinoline-1(2H)-carboxylate(I-244)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.55-0.60 (m, 2H), 0.62-0.77 (m, 2H), 1.11(d, J=6.60 Hz, 3H), 1.49-1.59 (m, 1H), 1.82-1.88 (m, 1H), 2.00-2.07 (m,1H), 2.39-2.49 (m, 1H), 2.58-2.67 (m, 1H), 3.79 (s, 3H), 4.62-4.68 (m,1H), 6.73-6.80 (m, 3H), 6.95-7.00 (m, 1H), 7.23-7.26 (m, 1H), 7.25-7.27(m, 1H), 7.43 (d, J=8.70 Hz, 1H). MS (ESI, pos. ion) m/z 338[M+H]⁺.

Example 40 methyl(S)-5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-245)

Formaldehyde (37% aqueous solution, 0.015 mL, 0.198 mmol) was added to asolution of (S)-methyl5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.010 g, 0.020 mmol) in methanol (1.0 mL), and the reaction mixturestirred for 2 h. The mixture was cooled to 0° C. and sodiumtriacetoxyborohydride (8.4 mg, 0.040 mmol) was added. The reactionmixture stirred at 0° C. and was allowed to warm to room temperatureovernight. The reaction mixture was partitioned between ethyl acetateand water. The aqueous phase was extracted with ethyl acetate and thecombined organic phases were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated to afford (S)-methyl5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.0095 g, 92%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.06(br d, J=6.74 Hz, 3H), 1.47-1.69 (m, 4H), 1.71-2.13 (m, 4H), 2.19 (s,3H), 2.71-2.90 (m, 2H), 3.72 (s, 3H), 3.93-4.13 (m, 1H), 4.32-4.45 (m,1H), 4.50-4.65 (m, 1H), 6.35-6.54 (m, 1H), 7.45-7.65 (m, 4H), 7.65-7.72(m, 1H), 7.97 (s, 1H), 8.11 (d, J=2.64 Hz, 1H). MS (ESI, pos. ion) m/z521 [M+H]⁺.

Example 41(S)-2-((1-acetyl-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzonitrile(I-246)

A mixture of(S)-2-((1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzonitrile(0.017 g, 0.044 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine(0.030 g, 0.101 mmol), XPhos Precatalyst 2nd Generation (3.47 mg, 4.41mol), and cesium carbonate (0.058 g, 0.177 mmol) in dioxane (2.0 mL) andwater (0.400 mL) was heated at 100° C. for 16 h. The reaction mixturewas filtered through Celite and concentrated to afford an orange oil.This material was purified via column chromatography on silica gel(Biotage 25 g column, gradient elution with 0-50% (90:10:1,dichloromethane/methanol/ammonium hydroxide)-dichloromethane) to afford(S)-2-((1-acetyl-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzonitrile(0.017 g, 82%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.04(d, J=7.04 Hz, 3H), 1.27-1.58 (m, 2H), 1.77-1.97 (m, 4H), 1.97-2.14 (m,4H), 2.17 (s, 3H), 2.19 (s, 3H), 2.81 (br d, J=11.43 Hz, 2H), 3.90-4.17(m, 1H), 4.62 (br s, 1H), 6.48 (br s, 1H), 7.14 (t, J=7.62 Hz, 1H),7.39-7.56 (m, 2H), 7.61 (d, J=8.50 Hz, 1H), 7.72 (s, 1H), 7.89 (dd,J=7.77, 1.61 Hz, 1H), 8.01 (s, 1H). MS (ESI, pos. ion) m/z 470 [M+H]⁺.

Example 42 (2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-247)

(2S)-Methyl5-cyclobutoxy-2-methyl-6-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from (2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylateaccording to the procedure outlined above for Example 40. ¹H NMR (400MHz, CD₃OD) δ ppm 1.17 (d, J=6.40 Hz, 3H), 1.25-1.48 (m, 2H), 1.55-1.65(m, 1H), 1.99-2.20 (m, 4H), 2.21-2.28 (m, 1H), 2.30-2.50 (m, 2H),2.75-2.99 (m, 2H), 3.01-3.20 (m, 3H), 3.30-3.40 (m, 1H), 3.55-3.72 (m,1H), 3.78 (s, 3H), 3.90-4.05 (m, 2H), 4.10-4.25 (m, 1H), 4.48-4.60 (m,1H), 7.20-7.30 (m, 2H), 7.95 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion)m/z 425[M+H]⁺.

Example 43 (2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(2-methyl-octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-248)

(2S)-Methyl5-cyclobutoxy-2-methyl-6-(1-(2-methyl-octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from (2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylateaccording to the procedure outlined above for Example 40. ¹H NMR (400MHz, CD₃OD) 1.17 (d, J=6.40 Hz, 3H), 1.28-1.48 (m, 2H), 1.55-1.70 (m,1H), 1.99-2.20 (m, 6H), 2.21-2.50 (m, 9H), 2.79-2.98 (m, 5H), 3.78 (s,3H), 4.05-4.15 (m, 1H), 4.45-4.55 (m, 1H), 4.85-4.95 (m, 1H), 7.20-7.30(m, 2H), 7.83 (s, 1H), 8.01 (s, 1H). MS (ESI, pos. ion) m/z 465 [M+H]⁺.

Example 44 (2S)-methyl5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-249)

(2S)-Methyl5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from (2S)-methyl5-(4-fluorophenoxy)-2-methyl-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylateaccording to the procedure outlined above for Example 40. ¹H NMR (400MHz, CD₃OD) δ ppm 1.15 (d, J=6.40 Hz, 3H), 1.48-1.65 (m, 1H), 2.01-2.10(m, 1H), 2.12-2.23 (m, 1H), 2.38-2.45 (m, 1H), 2.55-2.85 (m, 2H),2.92-3.05 (m, 3H), 3.20-3.30 (m, 1H), 3.40-4.60 (m, 1H), 3.82 (s, 3H),3.89-3.95 (m, 2H), 4.58-4.65 (m, 1H), 5.15-5.25 (m, 1H), 6.68-6.74 (m,2H), 6.95-7.02 (m, 2H), 7.48-6.60 (m, 2H), 7.89 (s, 1H), 7.99 (s, 1H).MS (ESI, pos. ion) m/z 465[M+H]⁺.

Example 45 (2S)-methyl5-(4-fluorophenoxy)-2-methyl-6-(1-(2-methyl-octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-250)

(2S)-Methyl5-(4-fluorophenoxy)-2-methyl-6-(1-(2-methyl-octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from (2S)-methyl5-(4-fluorophenoxy)-2-methyl-6-(1-(octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylateaccording to the procedure outlined above for Example 40. ¹H NMR (300MHz, CD₃OD) δ ppm 1.14 (d, J=6.60 Hz, 3H), 1.50-1.62 (m, 1H), 1.85-1.99(m, 2H), 2.01-2.20 (m, 3H), 2.25-2.45 (m, 6H), 2.55-2.75 (m, 5H),4.55-4.70 (m, 1H), 4.70-4.82 (m, 1H), 6.65-6.75 (m, 2H), 6.90-7.02 (m,2H), 7.48-7.52 (m, 2H), 7.75 (s, 1H), 7.89 (s, 1H). MS (ESI, pos. ion)m/z 505[M+H]⁺.

Example 46 (S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-ethylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-251)

(S)-Methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-ethylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from (S)-methyl5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateand acetaldehyde according to the procedure outlined above for Example40. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.96 (t, J=7.20 Hz, 3H), 1.05-1.20 (m,7H), 1.42-1.55 (m, 1H), 2.15-2.25 (m, 1H), 2.40-2.52 (m, 3H), 2.81-2.95(m, 1H), 3.01-3.15 (m, 2H), 3.41-3.52 (m, 2H), 3.68-3.71 (m, 1H), 3.78(s, 3H), 4.21-4.28 (m, 1H), 4.51-4.61 (m, 1H), 7.20-7.32 (m, 2H), 7.76(s, 1H), 7.99 (s, 1H). MS (ESI, pos. ion) m/z 411[M+H]⁺.

Example 47 (S)-methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-isopropylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-252)

(S)-Methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-isopropylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from (S)-methyl5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateand acetone according to the procedure outlined above for Example 40. ¹HNMR (400 MHz, CD₃OD) δ ppm 0.85-0.95 (m, 6H), 1.05-1.15 (m, 7H),1.45-1.55 (m, 1H), 2.15-2.52 (m, 3H), 2.80-2.90 (m, 1H), 3.01-3.11 (m,2H), 3.40-3.50 (m, 2H), 3.67-3.71 (m, 1H), 3.78 (s, 3H), 4.15-4.25 (m,1H), 4.51-4.62 (m, 1H), 7.20-7.35 (m, 2H), 7.76 (s, 1H), 7.97 (s, 1H).MS (ESI, pos. ion) m/z 425[M+H]⁺.

Example 48(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-ethylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-253)

(S)-1-(6-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-(1-ethylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanonewas synthesized from(S)-1-(5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanoneand acetaldehyde according to the procedure outlined above for Example40. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.97 (t, J=7.20 Hz, 3H), 1.05-1.18 (m,7H), 1.10-1.35 (m, 1H), 2.16 (s, 3H), 2.20-2.40 (m, 2H), 2.51 (q, J=7.20Hz, 2H), 2.88-2.98 (m, 1H), 3.07 (t, J=7.20 Hz, 1H), 3.15 (t, J=7.20 Hz,1H), 3.41-3.55 (m, 2H), 3.68-3.75 (m, 1H), 4.25-4.32 (m, 1H), 4.65-4.80(m, 1H), 7.01-7.12 (m, 1H), 7.37 (d, J=8.00 Hz, 1H), 7.81 (s, 1H), 8.02(s, 1H). MS (ESI, pos. ion) m/z 395[M+H]⁺.

Example 49(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-isopropylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-254)

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-isopropylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanonewas synthesized from(S)-1-(5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanoneand acetone according to the procedure outlined above for Example 40. ¹HNMR (400 MHz, CD₃OD) δ ppm 0.89-1.01 (m, 6H), 1.01-1.15 (m, 7H),1.21-1.35 (m, 1H), 2.16 (s, 3H), 2.25-2.45 (m, 3H), 2.85-2.95 (m, 1H),3.06 (t, J=7.20 Hz, 1H), 3.15 (t, J=7.20 Hz, 1H), 3.41-3.55 (m, 2H),3.68-3.73 (m, 1H), 4.21-4.29 (m, 1H), 4.65-4.81 (m, 1H), 7.01-7.12 (m,1H), 7.36 (d, J=8.00 Hz, 1H), 7.81 (s, 1H), 8.03 (s, 1H). MS (ESI, pos.ion) m/z 409[M+H]⁺.

Example 501-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(I-255)

Step 1.1-[(2S)-6-bromo-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one

A 20-mL microwave tube was charged with1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(200 mg, 0.70 mmol), 2-chloro-4-methylpyridine (180 mg, 1.41 mmol),N,N-dimethylformamide (15 mL), copper (I) iodide (133 mg, 0.70 mmol),and cesium carbonate (700 mg, 2.10 mmol). The reaction mixture washeated with microwave radiation for 8 h at 120° C. After cooling to roomtemperature, the resulting mixture was diluted with ethyl acetate (50mL), washed with water (3×15 mL) and brine (15 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified viacolumn chromatography on silica gel (eluting with 2:1, ethylacetate/petroleum ether) to afford1-[(2S)-6-bromo-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(111 mg, 42%) as a light yellow solid. MS (ESI, pos. ion) m/z 375, 377[M+H]⁺.

Step 2.1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one

A 50-mL round-bottom flask was purged and maintained with an inertatmosphere of nitrogen, and charged with1-[(2S)-6-bromo-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(111 mg, 0.30 mmol), 1,4-dioxane (15 mL),1-cyclopropyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (139mg, 0.59 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.04mmol), potassium carbonate (124 mg, 0.90 mmol), and water (5 mL). Theresulting mixture stirred overnight at 100° C. After cooling to roomtemperature, the solution was diluted with ethyl acetate (10 mL). Theaqueous layer was separated and extracted with ethyl acetate (2×20 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified via column chromatography on silica gel (eluting with 1:1,ethyl acetate/petroleum ether). The collected fractions were combinedand concentrated under vacuum. The crude product was further purified byPrep-HPLC with the following conditions (Waters I): Column, SunFire PrepC18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate)and acetonitrile (65% to 85% acetonitrile in 7 min, flow rate 20mL/min); Detector, UV 220&254 nm. This afforded1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(63.6 mg, 53%) as an off-white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm0.95-1.01 (m, 4H), 1.14 (d, J=6.30 Hz, 3H), 1.30-1.45 (m, 1H), 2.10-2.30(m, 5H), 2.34 (s, 3H), 2.55-2.70 (m, 1H), 3.55-3.65 (m, 1H), 4.68-4.85(m, 1H), 6.75 (s, 1H), 6.85-6.95 (m, 1H), 7.20-7.32 (m, 1H), 7.55-7.58(m, 1H), 7.72 (s, 1H), 7.89-7.93 (m, 2H). MS (ESI, pos. ion) m/z 403[M+H]⁺.

The following examples were made according to the procedure outlined forExample 50:

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(6-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-256)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.91-0.99 (m, 4H), 1.12 (d, J=6.60 Hz,3H), 1.25-1.45 (m, 1H), 2.10-2.30 (m, 5H), 2.37 (s, 3H), 2.55-2.68 (m,1H), 3.55-3.62 (m, 1H), 4.65-4.83 (m, 1H), 6.45 (d, J=8.40 Hz, 1H), 6.89(d, J=7.50 Hz, 1H), 7.20-7.35 (m, 1H), 7.50-7.62 (m, 2H), 7.73 (s, 1H),7.93 (s, 1H). MS (ESI, pos. ion) m/z 403 [M+H]⁺.

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(isoquinolin-1-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-257)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.68-0.71 (m, 2H), 0.83-0.90 (m, 2H), 1.19(d, J=6.60 Hz, 3H), 1.46 (m, 1H), 2.18-2.31 (m, 5H), 2.67 (m, 1H),3.43-3.48 (m, 1H), 4.75-4.80 (m, 1H), 7.36-7.44 (m, 1H), 7.57 (d, J=4.80Hz, 1H), 7.60-7.67 (m, 1H), 7.74 (s, 1H), 7.76-7.79 (m, 1H), 7.89 (m,3H), 7.91-7.98 (m, 1H), 8.61 (d, J=8.10 Hz, 1H). MS (ESI, pos. ion) m/z439[M+H]⁺.

Example 51(S)-1-(5-(2-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-258)

Step 1.1-[(2S)-6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one

A 50-mL round-bottom flask was purged and maintained with an inertatmosphere of nitrogen and charged with1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(350 mg, 1.23 mmol), N,N-dimethylformamide (10 mL),1,2-difluoro-4-nitrobenzene (415 mg, 2.61 mmol) and cesium carbonate(1.3 g, 3.99 mmol). The resulting mixture stirred for 3 h at 110° C.After cooling to room temperature, the reaction mixture was poured intodichloromethane (50 mL), washed with water (10 mL) and brine (10 mL),dried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was purified via column chromatography on silica gel(eluting with 5:1, ethyl acetate/petroleum ether) to afford1-[(2S)-6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(450 mg, 86%) of as yellow oil. MS (ESI, neg. ion) m/z 421, 423[M−H].

Step 2.1-[(2S)-5-(4-amino-2-fluorophenoxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one

A 100-mL round-bottom flask was purged and maintained with an inertatmosphere of nitrogen, and charged with1-[(2S)-6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(500 mg, 1.18 mmol), iron powder (331 mg, 5.91 mmol), ammonium chloride(128 mg, 2.37 mmol), tetrahydrofuran (9 mL), ethanol (3 mL), and water(9 mL). The resulting mixture stirred for 12 h at 80° C. and was thenfiltered. The filtrate was concentrated, and the residue was dilutedwith ethyl acetate, washed with water, dried over anhydrous sodiumsulfate, filtered, and concentrated to afford1-[(2S)-5-(4-amino-2-fluorophenoxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(370 mg, 80%) as a light brown solid. MS (ESI, pos. ion) m/z 393, 395[M+H]⁺.

Step 3.1-[(2S)-6-bromo-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one

A 100-mL round-bottom flask was charged with1-[(2S)-5-(4-amino-2-fluorophenoxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(370 mg, 0.92 mmol) and acetic acid (5 mL). Sodium nitrite (1.3 g, 18.8mmol) was added in portions, and the mixture stirred at room temperaturefor 30 minutes. Sodium bisulfite (2.0 g, 18.8 mmol) and ethanol (5 mL)were added, and the resulting mixture stirred for 12 h at roomtemperature. The reaction mixture was concentrated under vacuum, dilutedwith dichloromethane, washed with water and brine, dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified viacolumn chromatography on silica gel (eluting with 5:1, ethylacetate/petroleum ether) to afford1-[(2S)-6-bromo-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(300 mg, 86%) of as yellow oil. MS (ESI, pos. ion) m/z 378, 380 [M+H]⁺.

Step 4. (S)-tert-butyl4-(4-(1-acetyl-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A 100-mL round-bottom flask was purged and maintained with an inertatmosphere of nitrogen, and charged with1-[(2S)-6-bromo-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(300 mg, 0.79 mmol), 1,4-dioxane (18 mL), water (3 mL),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65 mg, 0.08mmol), cesium carbonate (776 mg, 2.37 mmol), and tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(378 mg, 1.00 mmol). The resulting mixture stirred for 12 h at 80° C.After cooling to room temperature, the reaction mixture was passedthrough a short pad of Celite and concentrated under vacuum. The residuewas purified via column chromatography on silica gel (eluting with 5:1,ethyl acetate/petroleum ether) to afford (S)-tert-butyl4-(4-(1-acetyl-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(370 mg, 85%) as yellow oil. MS (ESI, pos. ion) m/z 549 [M+H]⁺.

Step 5.(S)-1-(5-(2-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 100-mL round-bottom flask was charged with (S)-tert-butyl4-(4-(1-acetyl-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(370 mg, 0.67 mmol), dichloromethane (10 mL) and trifluoroacetic acid (4mL). The resulting solution stirred for 2 h at room temperature. The pHvalue of the solution was adjusted to 8 with saturated aqueous potassiumcarbonate solution. The resulting mixture was extracted with ethylacetate. The organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified via column chromatography on silica gel (eluting with 5:1,ethyl acetate/petroleum ether) to afford(S)-1-(5-(2-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(141 mg, 47%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.15 (d,J=6.60 Hz, 3H), 1.25-1.45 (m, 1H), 1.75-1.95 (m, 2H), 1.97-2.08 (m, 2H),2.15-2.35 (m, 5H), 2.65-2.89 (m, 3H), 3.09-3.20 (m, 2H), 4.15-4.29 (m,1H), 4.65-4.85 (m, 1H), 6.35-6.48 (m, 1H), 6.85-6.98 (m, 2H), 7.13-7.22(m, 1H), 7.27-7.42 (m, 1H), 7.61 (d, J=8.40 Hz, 1H), 7.81 (s, 1H), 7.99(s, 1H). MS (ESI, pos. ion) m/z 449[M+H]⁺.

The following examples were made according to the procedure outlined forExample 51:

(S)-methyl5-(2-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-259)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (d, J=6.80 Hz, 3H), 1.55-1.68 (m,1H), 1.78-1.92 (m, 2H), 1.97-2.13 (m, 3H), 2.45-2.55 (m, 1H), 2.60-2.79(m, 3H), 3.11-3.18 (m, 2H), 4.18-4.25 (m, 1H), 4.62-4.70 (m, 1H),6.38-6.42 (m, 1H), 6.85-6.95 (m, 2H), 7.15-7.25 (m, 1H), 7.50-7.62 (m,2H), 7.78 (s, 1H), 7.93 (s, 1H). MS (ESI, pos. ion) m/z 465[M+H]⁺.

(S)-cyclopropyl(5-(2-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-260)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.85 (m, 1H), 8.87-1.01 (m, 2H),1.10-1.20 (m, 4H), 1.39-1.50 (m, 1H), 1.78-1.90 (m, 2H), 1.95-2.09 (m,3H), 2.15-2.38 (m, 2H), 2.65-2.80 (m, 3H), 3.11-3.19 (m, 2H), 4.18-4.28(m, 1H), 4.75-4.85 (m, 1H), 6.41-6.48 (m, 1H), 6.85-6.99 (m, 2H),7.18-7.28 (m, 1H), 7.42 (d, J=8.40 Hz, 1H), 7.63 (d, J=8.80 Hz, 1H),7.81 (s, 1H), 8.01 (s, 1H). MS (ESI, pos. ion) m/z 475[M+H]⁺.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-261)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (d, J=6.40 Hz, 3H), 1.55-1.64 (m,1H), 2.05-2.14 (m, 1H), 2.45-2.52 (m, 1H), 2.63-2.72 (m, 1H), 3.82 (s,3H), 3.90-3.98 (m, 2H), 4.03-4.11 (m, 2H), 4.63-4.73 (m, 1H), 5.19-5.29(m, 1H), 6.35-6.42 (m, 1H), 6.83-6.95 (m, 2H), 7.17-7.25 (m, 1H),7.20-7.25 (m, 1H), 7.53-7.62 (m, 2H), 7.65-7.70 (m, 1H), 8.03 (s, 1H).MS (ESI, pos. ion) m/z 437[M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-262)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.60-0.70 (m, 1H), 0.75-0.90 (m, 2H),1.00-1.10 (m, 4H), 1.20-1.30 (m, 1H), 1.80-1.92 (m, 1H), 2.05-2.25 (m,2H), 2.55-2.65 (m, 1H), 3.72-3.80 (m, 2H), 3.85-3.95 (m, 2H), 4.65-4.75(m, 1H), 5.05-5.15 (m, 1H), 6.25-6.35 (m, 1H), 6.70-6.90 (m, 2H),7.05-7.15 (m, 1H), 7.30 (d, J=8.40 Hz, 1H), 7.51 (d, J=8.40 Hz, 1H),7.78 (s, 1H), 7.95 (s, 1H). MS (ESI, pos. ion) m/z 447[M+H]⁺.

The examples below were made according to the procedure outlined abovefor Example 51, with the following changes to Step 1: (1)1,2,5-trifluoro-3-nitrobenzene was used in place of1,2-difluoro-4-nitrobenzene; (2) potassium tert-butoxide was usedinstead of cesium carbonate; (3) tetrahydrofuran was used as the solventin place of DMF; (4) the reaction was run at 0° C. for 1 hour as opposedto 3 h at 110° C.

(S)-methyl5-(2,4-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-263)

¹H NMR (400 MHz, CDCl₃) δ ppm 1.15 (d, J=6.80 Hz, 3H), 1.55-1.65 (m,1H), 1.80-1.95 (m, 2H), 2.01-2.15 (m, 3H), 2.35-2.45 (m, 1H), 2.60-2.80(m, 3H), 3.20-3.30 (m, 2H), 4.08-4.20 (m, 1H), 4.60-4.70 (m, 1H),6.30-6.40 (m, 1H), 6.50-6.60 (m, 1H), 6.85-6.95 (m, 1H), 7.41 (d, J=8.80Hz, 1H), 7.60 (d, J=8.40 Hz, 1H), 7.69-7.62 (m, 2H). MS (ESI, pos. ion)m/z 483[M+H]⁺.

(S)-cyclopropyl(5-(2,4-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-264)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.70-0.80 (m, 1H), 0.89-1.03 (m, 2H),1.09-1.20 (m, 4H), 1.35-1.45 (m, 1H), 1.80-2.10 (m, 5H), 2.15-2.40 (m,2H), 2.68-2.80 (m, 3H), 3.10-3.20 (m, 2H), 4.20-4.30 (m, 1H), 4.75-4.85(m, 1H), 6.40-6.50 (m, 1H), 6.70-6.80 (m, 1H), 7.05-7.12 (m, 1H), 7.42(d, J=8.40 Hz, 1H), 7.61 (d, J=8.80 Hz, 1H), 7.80 (s, 1H), 8.01 (s, 1H).MS (ESI, pos. ion) m/z 493 [M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,4-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-265)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.70-0.82 (m, 1H), 0.89-1.02 (m, 2H),1.10-1.22 (m, 3H), 1.40-1.52 (m, 1H), 1.95-2.05 (m, 1H), 2.15-2.42 (m,2H), 2.68-2.80 (m, 1H), 3.65-3.85 (m, 2H), 4.10-4.30 (m, 2H), 4.75-4.85(m, 1H), 4.90-5.05 (m, 1H), 6.40-6.50 (m, 1H), 6.65-6.75 (m, 1H),7.05-7.15 (m, 1H), 7.43 (d, J=8.40 Hz, 1H), 7.55-7.65 (m, 1H), 7.80-8.10(m, 2H). MS (ESI, pos. ion) m/z 465[M+H]⁺.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,4-difluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-266)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (d, J=6.40 Hz, 3H), 1.56-1.66 (m,1H), 2.07-2.15 (m, 1H), 2.45-2.51 (m, 1H), 2.63-2.71 (m, 1H), 3.82 (s,3H), 3.92-3.97 (m, 2H), 4.06-4.12 (m, 2H), 4.65-4.71 (m, 1H), 7.51-7.56(m, 1H), 7.57-7.64 (m, 1H), 7.85 (m, 1H), 8.05 (s, 1H). MS (ESI, pos.ion) m/z 455[M+H]⁺.

The examples below were made according to the procedure outlined abovefor Example 51, with the following changes to Step 1: (1)1,2,3-trifluoro-4-nitrobenzene was used in place of1,2-difluoro-4-nitrobenzene; (2) potassium tert-butoxide was usedinstead of cesium carbonate; (3) tetrahydrofuran was used as the solventin place of DMF; (4) the reaction was run at 0° C. for 1 hour as opposedto 3 h at 110° C.

(S)-cyclopropyl(5-(2,3-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-267)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.80 (m, 1H), 0.85-1.01 (m, 2H),1.10-1.21 (m, 4H), 1.40-1.50 (m, 1H), 1.80-2.10 (m, 5H), 2.15-2.40 (m,2H), 2.68-2.82 (m, 3H), 3.10-3.25 (m, 2H), 4.20-4.34 (m, 1H), 4.75-4.85(m, 1H), 6.20-6.30 (m, 1H), 6.80-6.95 (m, 2H), 7.44 (d, J=8.40 Hz, 1H),7.62 (d, J=8.40 Hz, 1H), 7.79 (s, 1H), 7.99 (s, 1H). MS (ESI, pos. ion)m/z 493[M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-268)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.72-0.80 (m, 1H), 0.85-1.01 (m, 2H),1.10-1.20 (m, 4H), 1.40-1.52 (m, 1H), 1.95-2.05 (m, 1H), 2.15-2.45 (m,2H), 2.65-2.80 (m, 1H), 3.60-3.82 (m, 1H), 3.85-4.12 (m, 3H), 4.75-4.85(m, 1H), 5.15-5.30 (m, 1H), 6.20-6.30 (m, 1H), 6.82-6.95 (m, 2H), 7.44(d, J=8.80 Hz, 1H), 7.62 (d, J=8.40 Hz, 1H), 7.80-7.90 (m, 1H),8.02-8.12 (m, 1H). MS (ESI, pos. ion) m/z 465[M+H]⁺.

(S)-methyl5-(2,3-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-269)

¹H NMR (400 MHz, CD₃OD) 1.05 (d, J=6.80 Hz, 3H), 1.55-1.65 (m, 1H),1.65-1.80 (m, 2H), 1.85-2.05 (m, 3H), 2.30-2.42 (m, 1H), 2.50-2.65 (m,3H), 3.01-3.10 (m, 2H), 3.71 (s, 1H), 4.05-4.15 (m, 1H), 4.52-4.62 (m,1H), 6.05-6.15 (M, 1H), 6.68-6.78 (m, 2H), 7.41 (d, J=8.80 Hz, 1H), 7.51(d, J=8.80 Hz, 1H), 7.64 (s, 1H), 7.83 (s, 1H). MS (ESI, pos. ion) m/z483[M+H]⁺.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-difluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-270)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.09 (d, J=6.40 Hz, 3H), 1.60-1.66 (m,1H), 2.08-2.13 (m, 1H), 2.46-2.52 (m, 1H), 2.63-2.71 (m, 1H), 3.82 (s,3H), 3.92-3.98 (m, 2H), 4.06-4.13 (m, 2H), 4.64-4.71 (m, 1H), 5.21-5.28(m, 1H), 6.21-6.28 (m, 1H), 6.84-6.91 (m, 2H), 7.54 (d, J=8.80 Hz, 1H),7.63 (d, J=8.40 Hz, 1H), 7.85 (s, 1H), 8.02 (s, 1H). MS (ESI, pos. ion)m/z 455[M+H]⁺.

The examples below were made according to the procedure outlined abovefor Example 51, with the following changes to Step 1: (1)1,2,4-trifluoro-5-nitrobenzene was used in place of1,2-difluoro-4-nitrobenzene; (2) potassium tert-butoxide was usedinstead of cesium carbonate; (3) tetrahydrofuran was used as the solventin place of DMF; (4) the reaction was run at 0° C. for 1 hour as opposedto 3 h at 110° C.

(S)-methyl6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-271)

¹H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.16 (m, 3H), 1.49-1.55 (m, 1H),1.95-2.06 (m, 1H), 2.36-2.44 (m, 2H), 3.61-3.68 (m, 2H), 3.69-3.75 (m3H), 3.77-3.85 (m, 2H), 4.46 (m, 1H), 5.02-5.20 (m, 1H), 6.35-6.61 (m,1H), 6.85-7.11 (m, 1H), 7.18-7.43 (m, 1H), 7.58 (s, 2H), 7.79 (s, 1H),8.13 (s, 1H). MS (ESI, pos. ion) m/z 455[M+H]⁺.

(S)-(6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-272)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.59-0.72 (m, 1H), 0.82-0.93 (m, 2H),1.02-1.09 (m, 4H), 1.30-1.43 (m, 1H), 1.88-1.95 (m, 1H), 2.13-2.23 (m,1H), 2.60-2.70 (m, 1H), 3.53-3.69 (m, 1H), 3.82-4.05 (m, 3H), 4.69-4.74(m, 1H), 5.13-5.19 (m, 1H), 6.03-6.11 (m, 1H), 7.08-7.19 (m, 1H),7.34-7.38 (m, 1H), 7.50-7.55 (m, 1H), 7.73-7.77 (m, 1H), 7.93-7.99 (m,1H). MS (ESI, pos. ion) m/z 465 [M+H]⁺.

(S)-methyl5-(2,5-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-273)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.18 (d, J=6.80 Hz, 3H), 1.50-1.59 (m,1H), 2.11-2.22 (m, 5H), 2.45-2.54 (m, 1H), 2.63-2.72 (m, 1H), 3.04-3.11(m, 2H), 3.39-3.46 (m, 2H), 3.83 (m, 3H), 4.49-4.59 (m, 1H), 4.66-4.71(m, 1H), 6.08-6.16 (m, 1H), 6.62-6.74 (m, 1H), 7.18-7.27 (m, 1H), 7.56(d, J=8.40 Hz, 1H), 7.65 (d, J=8.40 Hz, 1H), 7.82 (s, 1H), 7.96 (s, 1H),8.57 (br s, 1H). MS (ESI, pos. ion) m/z 483 [M+H]⁺.

(S)-cyclopropyl(5-(2,5-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-274)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.82 (m, 1H), 0.91-1.02 (m, 2H),1.11-1.22 (m, 4H), 1.41-1.52 (m, 1H), 1.80-1.91 (m, 2H), 1.98-2.07 (m,3H), 2.21-2.32 (m, 1H), 2.33-2.41 (m, 1H), 2.64-2.79 (m, 3H), 3.11-3.15(m, 2H), 4.18-4.29 (m, 1H), 4.71-4.83 (m, 1H), 6.12-6.21 (m, 1H),6.63-6.74 (m, 1H), 7.22-7.29 (m, 1H), 7.45 (d, J=8.40 Hz, 1H), 7.63 (d,J=8.40 Hz, 1H), 7.80 (m, 1H). MS (ESI, pos. ion) m/z 493 [M+H]⁺.

Example 52(S)-1-(5-(3,4-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-275) and(S)-1-(5-(2,5-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-276)

Step 1.(S)-(6-bromo-5-(2,5-difluoro-4-nitrophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(6-bromo-5-(4,5-difluoro-2-nitrophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

A 100-mL, 3-necked round-bottom flask was charged with a solution of(S)-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(2.00 g, 6.45 mmol) in tetrahydrofuran (20 mL). Potassium tert-butoxide(0.797 g, 7.10 mmol) was added in portions at 0° C. and the mixturestirred for 5 minutes. 1,2,4-Trifluoro-5-nitrobenzene (1.72 g, 9.71mmol) was then added, and the resulting mixture stirred at 0° C. for 3h. Hydrochloric acid (1 N aqueous, 10 mL) was added, and the aqueousphase was separated and extracted with ethyl acetate (2×15 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (eluting with 1:10, ethylacetate/petroleum ether) to afford a mixture of(S)-(6-bromo-5-(2,5-difluoro-4-nitrophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(6-bromo-5-(4,5-difluoro-2-nitrophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(2.1 g, 70%) as yellow oil. MS (ESI, pos. ion) m/z 467,469[M+H]⁺

Step 2.(S)-(5-(4-amino-2,5-difluorophenoxy)-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(5-(2-amino-4,5-difluorophenoxy)-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

A 100-mL, round-bottom flask was charged with a mixture of(S)-(6-bromo-5-(2,5-difluoro-4-nitrophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(6-bromo-5-(4,5-difluoro-2-nitrophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(2.1 g, 4.49 mmol), iron powder (1.26 g, 22.5 mmol), ammonium chloride(0.476 g, 8.90 mmol), tetrahydrofuran (10 mL), ethanol (10 mL), andwater (3 mL). The resulting mixture stirred overnight at 80° C. Aftercooling to room temperature, the reaction mixture was filtered, and thefiltrate was extracted with ethyl acetate (2×15 mL). The combinedorganic layers were concentrated under vacuum to afford a mixture of(S)-(5-(4-amino-2,5-difluorophenoxy)-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(5-(2-amino-4,5-difluorophenoxy)-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(1.8 g, 96%) as brown oil, which was directly used in next step withoutfurther purification. MS (ESI, pos. ion) m/z 437,439[M+H]⁺

Step 3.(S)-(6-bromo-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(6-bromo-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

A 100-mL, round-bottom flask was charged with a mixture of(S)-(5-(2-amino-4,5-difluorophenoxy)-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(5-(4-amino-2,5-difluorophenoxy)-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(1.8 g, 4.12 mmol) and N,N-dimethylformamide (10 mL). A solution oftert-butyl nitrite (1.2 g, 11.64 mmol) in N,N-dimethylformamide (10 mL)was added dropwise, and the resulting solution stirred for 4 h at 50° C.After cooling to room temperature, the reaction mixture was diluted withethyl acetate (100 mL). The organic layer was washed with water (3×20mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered,and concentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with 1:10, ethyl acetate/petroleumether) to afford a mixture of(S)-(6-bromo-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(6-bromo-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.600 g, 35%) as yellow oil. MS (ESI, pos. ion) m/z 422,424[M+H]⁺.

Step 4. tert-butyl4-[4-[(2S)-1-acetyl-5-(3,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]piperidine-1-carboxylateand tert-butyl4-[4-[(2S)-1-acetyl-5-(2,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]piperidine-1-carboxylate

A 100-mL, round-bottom flask was charged with a mixture of(S)-1-(6-bromo-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanoneand(S)-1-(6-bromo-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.130 g, 0.33 mmol), tert-butyl4-[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(0.149 mg, 0.39 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichlormethane adduct (0.027 g, 0.03 mmol), potassium carbonate (0.137mg, 0.99 mmol), 1,4-dioxane (15 mL) and water (3 mL). The resultingmixture stirred overnight at 100° C. After cooling to room temperature,the reaction mixture was passed through a short pad of Celite, and thefiltrate was concentrated under vacuum. The residue was purified viapreparative thin layer chromatography (eluting with 1:1, ethylacetate/petroleum ether) to afford a mixture of tert-butyl4-[4-[(2S)-1-acetyl-5-(3,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]piperidine-1-carboxylateand tert-butyl4-[4-[(2S)-1-acetyl-5-(2,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]piperidine-1-carboxylate(0.160 g, 86%) as yellow oil. MS (ESI, pos. ion) m/z 567[M+H]⁺.

Step 5.(S)-1-(5-(3,4-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanoneand(S)-1-(5-(2,5-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 100-mL, round-bottom flask was charged with a mixture of(S)-tert-butyl4-(4-(1-acetyl-5-(3,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateand (S)-tert-butyl4-(4-(1-acetyl-5-(2,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.160 g, 0.28 mmol), dichloromethane (9 mL), and trifluoroacetic acid(3 mL). The resulting solution stirred for 2 h at room temperature. ThepH of the solution was adjusted to 7-8 with saturated aqueous potassiumcarbonate solution. The aquoues layer was separated and extracted withdichloromethane (3×10 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified by preparative-HPLC with the following conditions(Waters I): Column: XBridge RP C18, 19×150 mm, 5 um; Mobile Phase: water(0.05% ammonium bicarbonate) and acetonitrile; (5% to 60% acetonitrilein 7.0 min, flow rate: 20 mL/min); Detector, UV 254&220 nm. Thisafforded:

(S)-1-(5-(3,4-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.031 g, 24%) as a light yellow solid. ¹H NMR (300 MHz, CD₃OD) δ ppm1.10 (d, J=6.60 Hz, 3H), 1.18-1.41 (m, 1H), 1.72-1.89 (m, 2H), 1.92-2.01(m, 2H), 2.10-2.31 (m, 2H), 2.16 (s, 3H), 2.58-2.74 (m, 3H), 3.3.08-3.12(m, 2H), 4.10-4.23 (m, 1H), 4.63-4.83 (m, 1H), 6.45-6.52 (m, 1H),6.60-6.73 (m, 1H), 7.11 (q, J=9.30 Hz, 1H), 7.20-7.33 (m, 1H), 7.57 (d,J=8.40 Hz, 1H), 7.74 (s, 1H), 7.92 (s, 1H). MS (ESI, pos. ion) m/z467[M+H]⁺.

and

(S)-1-(5-(2,5-difluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.006 g, 5%) as a light yellow solid. ¹H NMR (300 MHz, CD₃OD) δ ppm1.11 (d, J=6.60 Hz, 3H), 1.25-1.49 (m, 1H), 1.71-1.87 (m, 2H), 1.92-2.05(m, 2H), 2.19 (s, 3H), 2.15-2.38 (m, 2H), 2.59-2.73 (m, 3H), 3.11 (d,J=12.60 Hz, 2H), 4.10-4.22 (m, 1H), 4.65-4.85 (m, 1H), 6.05-6.15 (m,1H), 6.57-6.71 (m, 1H), 7.13-7.21 (m, 1H), 7.22-7.39 (m, 1H), 7.58 (d,J=8.40 Hz, 1H), 7.75 (s, 1H), 7.93 (s, 1H). MS (ESI, pos. ion) m/z467[M+H]⁺.

Example 53(S,E)-1-(5-(2-chlorovinyloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-277)

Step 1.1-[(2S)-6-bromo-5-(2,2-dichloroethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one

A 40-mL resealable tube was charged with1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(90 mg, 0.32 mmol), 2,2-dichloroethyl methanesulfonate (82 mg, 0.42mmol), potassium carbonate (135 mg, 0.96 mmol), andN,N-dimethylformamide (10 mL). The resulting mixture stirred for 48 h at110° C. After cooling to room temperature, the reaction mixture wasfiltered and concentrated under reduced pressure. The residue waspurified by preparative thin layer chromatography (eluting withpetroleum ether/ethyl acetate, 10:1 then 1:2) to afford1-[(2S)-6-bromo-5-(2,2-dichloroethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(56 mg, 46%) as light yellow oil. MS (ESI, pos. ion) m/z 31, 383 [M+H]⁺.

Step 2.(S,E)-1-(5-(2-chlorovinyloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 50-mL round-bottom flask was purged and maintained with an inertatmosphere of nitrogen and charged with1-[(2S)-6-bromo-5-(2,2-dichloroethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(43 mg, 0.11 mmol),1-cyclopropyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40mg, 0.17 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.01mmol), potassium carbonate (31 mg, 0.22 mmol), 1,4-dioxane (24 mL), andwater (4 mL). The resulting mixture stirred for 15 h at 100° C. in anoil bath. After cooling to room temperature, the reaction mixture waspassed a short pad of celite and concentrated under vacuum. The residuewas purified by preparative thin layer chromatography (eluting withdichloromethane/methanol, 50:1 then 20:1) to afford(S,E)-1-(5-(2-chlorovinyloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(12 mg, 26%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.05-1.15(m, 7H), 1.35-1.58 (m, 1H), 2.21 (s, 3H), 2.25-2.50 (m, 2H), 2.80-2.93(m, 1H), 3.65-3.75 (m, 1H), 4.61 (s, 1H), 4.70-4.85 (m, 1H), 5.52 (d,J=4.20 Hz, 1H), 6.52 (d, J=4.20 Hz, 1H), 7.15-7.25 (m, 1H), 7.54 (d,J=8.40 Hz, 1H), 7.89 (s, 1H), 8.07 (s, 1H). MS (ESI, pos. ion) m/z372[M+H]⁺.

Example 54((2S)-5-cyclobutoxy-6-(2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-7-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-278)

Step 1. 5-Amino-1-(2-hydroxyethyl)-1H-pyrazole-4-carbonitrile

A 100-mL round-bottom flask was charged with2-(ethoxymethylene)malononitrile (4.88 g, 39.96 mmol), ethanol (50 mL)and 2-hydrazinylethan-1-ol (4.4 g, 57.82 mmol). The resulting solutionstirred for 10 h at 95° C. After cooling to room temperature, thereaction mixture was concentrated under vacuum. The residue was purifiedvia column chromatography on silica gel (eluting with 9:1,dichloromethane/methanol) to afford5-amino-1-(2-hydroxyethyl)-1H-pyrazole-4-carbonitrile (3.9 g, 63%) as ayellow solid. MS (ESI, pos. ion) m/z 153 [M+H]⁺.

Step 2. 2,3-dihydro-1H-imidazo[1,2-b]pyrazole

A 250-mL 3-necked round-bottom flask was charged with5-amino-1-(2-hydroxyethyl)-1H-pyrazole-4-carbonitrile (6.00 g, 39.4mmol) and concentrated sulfuric acid (80 mL). The resulting solutionstirred overnight at 170° C. After cooling to 0° C. with an ice/waterbath, the pH of the solution was adjusted to 8 with sodium hydroxide.The resulting solution was extracted with chloroform (4×500 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (eluting with 1:4, ethylacetate/petroleum ether). The crude product was further purified byre-crystallization with diethyl ether to afford2,3-dihydro-1H-imidazo[1,2-b]pyrazole (2.0 g, 46%) as a yellow solid. MS(ESI, pos. ion) m/z 110 [M+H]⁺.

Step 3. 7-bromo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole hydrobromide

A 100-mL round-bottom flask was charged with2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.7 g, 15.6 mmol) and acetic acid(5 mL). A solution of bromine (7.39 g, 46.2 mmol) in acetic acid (47 mL)was then added slowly. The resulting solution stirred for 3 h at roomtemperature. The reaction mixture was filtered and the filtrate wasconcentrated under vacuum to afford7-bromo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole hydrobromide (3.0 g, 72%)as a yellow solid. MS (ESI, pos. ion) m/z 188, 190 [M+H]⁺.

Step 4. tert-butyl7-bromo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-carboxylate

A 50-mL round-bottom flask was charged with a solution of7-bromo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole hydrobromide (100 mg, 0.53mmol) in dichloromethane (5 mL). Sodium hydride (30 mg, 1.20 mmol) wasadded, and the reaction mixture stirred at room temperature for 15 min.Di-tert-butyl dicarbonate (232 mg, 1.06 mmol) and4-dimethylaminopyridine (6.5 mg, 0.05 mmol) were added, and theresulting mixture stirred for 3.5 h at room temperature. The reactionmixture was poured into 10 mL of water and the layers were separated.The aqueous layer was extracted with ethyl acetate (3×50 mL). Theorganic layers were combined, washed with brine (3×20 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith 35% ethyl acetate-petroleum ether) to afford tert-butyl7-bromo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-carboxylate (100 mg,65%) as a white solid. MS (ESI, pos. ion) m/z 288, 290 [M+H]⁺.

Step 5.(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline

A 100-mL round-bottom flask was charged with(2S)-6-bromo-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline(1.54 g, 4.25 mmol), bis(pinacolato)diboron (3.22 g, 12.68 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (347 mg, 0.04 mmol), potassium acetate (1.04 g,10.60 mmol), and 1,4-dioxane (15 mL). The resulting mixture stirredovernight at 80° C. After cooling to room temperature, the reactionmixture was poured into 50 mL of water and the layers were separated.The aqueous layer was extracted with ethyl acetate (3×100 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (eluting with 9% ethylacetate-petroleum ether) to afford(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline(0.9 g, 55%) as yellow oil. MS (ESI, pos. ion) m/z 386 [M+H]⁺.

Step 6. tert-butyl7-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydroimidazo[1,2-b]pyrazole-1-carboxylate

An 8-mL resealable tube was charged with(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline(60 mg, 0.15 mmol), tert-butyl7-bromo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-carboxylate (45 mg, 0.16mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (11 mg, 0.02 mmol), sodium carbonate (30 mg, 0.28mmol), 1,4-dioxane (1.5 mL) and water (0.5 mL). The resulting mixturestirred overnight at 80° C. After cooling to room temperature, thereaction mixture was poured into 20 mL of ethyl acetate. The organiclayer was separated and washed with water and brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith 40% ethyl acetate-petroleum ether) to afford tert-butyl7-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydroimidazo[1,2-b]pyrazole-1-carboxylate(50 mg, 69%) of as a black solid. MS (ESI, pos. ion) m/z 493 [M+H]⁺.

Step 7.((2S)-5-cyclobutoxy-6-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

An 8-mL vial was charged with tert-butyl7-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydroimidazo[1,2-b]pyrazole-1-carboxylate(50 mg, 0.10 mmol), dichloromethane (3 mL) and trifluoroacetic acid (1mL). The resulting solution stirred for 4 h at room temperature. Thereaction mixture was concentrated under vacuum. The residue was purifiedvia preparative thin layer chromatography (eluting with 30% ethylacetate-petroleum ether) to afford((2S)-5-cyclobutoxy-6-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(11.7 mg, 20%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.65-0.75(m, 1H), 0.85-0.95 (m, 2H), 1.05-1.15 (m, 4H), 1.20-1.45 (m, 2H),1.58-1.72 (m, 1H), 1.85-1.95 (m, 1H), 1.98-2.45 (m, 6H), 3.01-3.09 (m,1H), 3.99-4.09 (m, 2H), 4.10-4.22 (m, 3H), 4.65-4.75 (m, 1H), 7.14 (d,J=8.00 Hz, 1H), 7.30 (d, J=8.00 Hz, 1H). 7.65 (s, 1H). MS (ESI, pos.ion) m/z 393 [M+H]⁺.

Example 55((2S)-5-cyclobutoxy-2-methyl-6-(1-(methylsulfonyl)-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-7-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-279)

((2S)-5-Cyclobutoxy-2-methyl-6-(1-(methylsulfonyl)-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-7-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanonewas prepared according to the procedure outlined above for(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline(Example 54) with the following changes: (1) in Step 4, triethylaminewas used as the base instead of sodium hydride, methanesulfonyl chloridewas substituted for di-tert-butyl dicarbonate, and DMAP was not added(2) Step 7 (Boc-deprotection) was eliminated. ¹H NMR (400 MHz, CD₃OD) δppm 0.72 (d, J=7.60 Hz, 1H), 0.85-0.96 (m, 2H), 1.14 (d, J=7.60 Hz, 4H),1.28-1.46 (m, 2H), 1.55-1.60 (m, 1H), 1.88-2.21 (m, 5H), 2.21-2.33 (m,2H), 2.95-3.05 (m, 1H), 3.08 (s, 3H), 4.05-4.18 (m, 1H), 4.26-4.51 (m,2H), 4.51-4.69 (m, 2H), 4.70-4.80 (m, 1H), 7.13 (d, J=8.40 Hz, 1H), 7.24(d, J=8.00 Hz, 1H), 7.59 (s, 1H). MS (ESI, pos. ion) m/z 471[M+H]⁺.

Example 56 methyl(S)-5-cyclobutoxy-6-(2-(4-hydroxypiperidin-4-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-280)

Step 1. tert-butyl4-(4-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate

n-Butyllithium (1.6 M in hexanes, 1.48 mL, 2.37 mmol) was added dropwiseto a −78° C. solution of 2,4-dibromothiazole (0.524 g, 2.16 mmol) indichloromethane (11 mL). The mixture stirred at −78° C. for 20 minutes,and then tert-butyl 4-oxopiperidine-1-carboxylate (0.516 g, 2.59 mmol)was added in 8 portions. The reaction mixture stirred at −78° C. for 10minutes. The cooling bath was removed, and the reaction was allowed towarm to rt over 1 h. The reaction mixture was cooled to −30° C. and wasthen quenched by the addition of saturated aqueous ammonium chloridesolution. The aqueous phase was separated and extracted withdichloromethane, and the combined organic phases were dried overanhydrous sodium sulfate, filtered, and concentrated. The residue waspurified via column chromatography on silica gel (Biotage 50 g column,gradient elution with 5-60% ethyl acetate-hexane) to afford tert-butyl4-(4-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (0.744 g,95%). MS (ESI, pos. ion) m/z 363, 365 [M+H]⁺.

Step 2. (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of (S)-methyl6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.534 g, 1.51 mmol), bis(pinacolato)diboron (0.421 g, 1.66 mmol),potassium acetate (0.370 g, 3.77 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.123 g, 0.151 mmol) in 1,4-dioxane (5.0 mL) washeated at 80° C. overnight. The reaction mixture was cooled to roomtemperature, filtered through a pad of Celite, and concentrated. Theresidue was purified via column chromatography on silica gel (Biotage 25g column, gradient elution with 5-10% ethyl acetate-hexane) to afford(S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.217 g, 36%) as a colorless oil. MS (ESI, pos. ion) m/z 402 [M+H]⁺.

Step 3. (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.109 g, 0.273 mmol), tert-butyl4-(4-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (0.090 g,0.248 mmol), XPhos Precatalyst 2nd Generation (0.019 g, 0.025 mmol), andcesium carbonate (0.242 g, 0.743 mmol) in 1,4-dioxane (1.0 mL) and water(0.2 mL) was heated at 100° C. for 2.5 h. The reaction mixture wascooled to room temperature, filtered through a pad of Celite, andconcentrated. The residue was purified via column chromatography onsilica gel (Biotage 25 g column, gradient elution with 5-50% ethylacetate-hexane) to afford (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.128 g, 93%). MS (ESI, pos. ion) m/z 558 [M+H]⁺.

Step 4. methyl(S)-5-cyclobutoxy-6-(2-(4-hydroxypiperidin-4-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

HCl (4 M in 1,4-dioxane, 0.58 mL, 2.30 mmol) was added to a solution of(S)-methyl6-(2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.128 g, 0.230 mmol) in 1,4-dioxane (1.0 mL), and the reaction mixturestirred at rt for 1 h. The reaction mixture was concentrated and theresidue was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate solution. The aqueous phase was separated andextracted with ethyl acetate. The combined organic phases were driedover anhydrous sodium sulfate, filtered, and concentrated. The residuewas dissolved in dichloromethane and then filtered through a plug ofsilica gel (eluting with 10% ethanol-ethyl acetate). The filtrate wasconcentrated to afford methyl(S)-5-cyclobutoxy-6-(2-(4-hydroxypiperidin-4-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(62 mg, 59%). ¹H NMR (300 MHz, DMSO-d6) δ ppm 1.11 (d, J=6.45 Hz, 3H),1.22-1.72 (m, 6H), 1.93-2.24 (m, 7H), 2.39-2.49 (m, 2H), 2.71-2.96 (m,4H), 3.69 (s, 3H), 4.05-4.20 (m, 1H), 4.47 (dq, J=13.05, 6.50 Hz, 1H),5.88 (s, 1H), 7.33 (d, J=8.79 Hz, 1H), 7.69 (d, J=8.50 Hz, 1H), 7.77 (s,1H). MS (ESI, pos. ion) m/z 458 [M+H]⁺.

Example 57 methyl(S)-5-cyclobutoxy-6-(2-(4-fluoropiperidin-4-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-281)

Step 1. tert-butyl4-(4-bromothiazol-2-yl)-4-fluoropiperidine-1-carboxylate

Diethylaminosulfur trifluoride (DAST) (0.083 mL, 0.627 mmol) was addedto a 0° C. of tert-butyl4-(4-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (0.207 g,0.570 mmol) in dichloromethane (2.8 mL). After 5 minutes, the coolingbath was removed and the reaction mixture was allowed to stir at roomtemperature overnight. Saturated aqueous sodium bicarbonate solution wasadded, and the aqueous phase was separated and extracted withdichloromethane. The combined organic phases were dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified viacolumn chromatography on silica gel (Biotage 25 g column, gradientelution with 5-50% ethyl acetate-hexane) to afford tert-butyl4-(4-bromothiazol-2-yl)-4-fluoropiperidine-1-carboxylate (0.163 g, 78%)as a colorless, waxy solid. MS (ESI, pos. ion) m/z 387, 389 [M+Na]⁺.

Step 2. (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.099 g, 0.247 mmol), tert-butyl4-(4-bromothiazol-2-yl)-4-fluoropiperidine-1-carboxylate (0.082 g, 0.224mmol), XPhos Precatalyst 2nd Generation (0.018 g, 0.022 mmol), andcesium carbonate (0.219 g, 0.673 mmol) in 1,4-dioxane (1.0 mL) and water(0.2 mL) was heated at 100° C. for 2 h. The reaction mixture was cooledto room temperature, filtered through a pad of Celite, and concentrated.The residue was purified via column chromatography on silica gel(Biotage 25 g column, gradient elution with 25-50% ethyl acetate-hexane)to afford (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.072 g, 57%). MS (ESI, pos. ion) m/z 558 [M+H]⁺.

Step 3. methyl(S)-5-cyclobutoxy-6-(2-(4-hydroxypiperidin-4-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

HCl (4 M in 1,4-dioxane, 0.32 mL, 1.28 mmol) was added to a solution of(S)-methyl6-(2-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.072 g, 0.128 mmol) in 1,4-dioxane (0.5 mL), and the reaction mixturestirred at rt for 1 h. The reaction mixture was concentrated and theresidue was purified by mass triggered preparatory HPLC. Theproduct-containing fractions were combined and concentrated in a Genevacto afford the methyl(S)-5-cyclobutoxy-6-(2-(4-hydroxypiperidin-4-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate.MS (ESI, pos. ion) m/z 460 [M+H]⁺.

Example 58 Methyl(S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-282)

Step 1. Methyl(S)-6-bromo-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of (S)-methyl6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (2.00g, 6.66 mmol), (4-fluorophenyl)boronic acid (1.865 g, 13.33 mmol),copper (II) acetate (1.33 g, 7.33 mmol), 4 Å molecular sieves (1 g),triethylamine (0.93 mL, 6.66 mmol), and pyridine (1.08 mL, 13.33 mmol)in dichloromethane (30 mL) was stirred opened to air at rt for two days.The reaction mixture was filtered through Celite and the filtrate wasconcentrated to afford a brown oil. This material was purified viacolumn chromatography on silica gel (Biotage 25 g column, gradientelution with 0-10% ethyl acetate-hexane) to afford methyl(S)-6-bromo-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(1.81 g, 69%) as a colorless film. MS (ESI, pos. ion) m/z 394, 396[M+H]⁺.

Step 2.Methyl-(S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of methyl(S)-6-bromo-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.100 g, 0.254 mmol), tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(0.106 g, 0.304 mmol), XPhos Precatalyst 2nd Generation (0.004 g, 0.005mmol), and cesium carbonate (0.246 g, 0.761 mmol) in 1,4-dioxane (2.0mL) and water (0.40 mL) was heated at 100° C. for 16 h. The reactionmixture was filtered through Celite and concentrated to afford a greenoil. This material was purified via column chromatography on silica gel(Biotage 10 g column, gradient elution with 25-50% ethyl acetate-hexane)to afford methyl(S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.098 g, 72%) as a colorless oil. MS (ESI, pos. ion) m/z 537 [M+H]⁺.

Step 3. Methyl(S)-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Trifluoroacetic acid (1.0 mL, 6.49 mmol) was added to a solution of(S)-methyl6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3-chloro-4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.098 g, 0.033 mmol) in dichloromethane (1.0 mL) and the reactionmixture stirred at rt for 2 h. The mixture was then concentrated and theresidue was partitioned between dichloromethane and saturated aqueoussodium bicarbonate solution. The organic phase was separated, dried overanhydrous sodium sulfate, filtered, and concentrated to afford methyl(S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.105 g, 100%) as an off-white solid. MS (ESI, pos. ion) m/z 437[M+H]⁺.

Step 4. Methyl(S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

Methyl(S)-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(105 mg, 0.241 mmol) was dissolved in methanol and formaldehyde (179 μL,2.41 mmol) was added. The reaction was stirred for 4 h at ambienttemperature and then cooled to 0° C. Sodium triacetoxyborohydride (0.102g, 0.481 mmol) was added and the reaction was slowly warmed to ambienttemperature. After 16 h the reaction was complete, and the reactionmixture was partitioned between ethyl acetate and water. The aqueousphase was separated and extracted with ethyl acetate, and the combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated to afford methyl(S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.086 g, 79%) as a pale orange oil. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.13(d, J=6.45 Hz, 3H) 1.18-1.20 (m, 1H) 1.20-1.33 (m, 1H) 1.55 (br dd,J=13.34, 5.42 Hz, 1H) 1.94-2.18 (m, 4H) 2.22-2.49 (m, 1H) 2.49-2.69 (m,1H) 3.81 (s, 3H) 4.26 (br s, 1H) 4.61-4.89 (m, 2H) 5.13-5.32 (m, 1H)6.63-6.82 (m, 2H) 6.83-7.01 (m, 2H) 7.40 (d, J=8.79 Hz, 1H) 7.54-7.67(m, 2H) 7.79-8.02 (m, 1H). MS (ESI, pos. ion) m/z 451 [M+H]⁺.

Example 59 Methyl(S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-283)

Methyl(S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from methyl(S)-6-bromo-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate,and tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateaccording to the procedure outlined above for Example 58. ¹H NMR (300MHz, CDCl₃) δ ppm 0.74-1.01 (m, 1H), 1.14 (d, J=6.74 Hz, 3H), 1.47-1.82(m, 2H), 1.99-2.07 (m, 1H), 2.31 (br s, 1H), 2.44 (dt, J=17.00, 5.72 Hz,1H), 2.52-2.72 (m, 1H), 2.77 (s, 3H), 3.16 (br s, 1H), 3.27-3.62 (m,2H), 3.82 (s, 3H), 4.43 (br s, 1H), 4.57-4.84 (m, 2H), 4.85-5.10 (m,1H), 6.68-6.75 (m, 2H), 6.86-6.98 (m, 2H), 7.27 (s, 1H), 7.41 (d, J=8.50Hz, 1H), 7.57-7.78 (m, 2H). MS (ESI, pos. ion) m/z 479 [M+H]⁺.

Example 60 Methyl(S)-5-cyclobutoxy-2-methyl-6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-284)

Step 1. Methyl(S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of methyl(S)-6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.096 g, 0.254 mmol), tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(0.113 g, 0.325 mmol), and cesium carbonate (0.264 g, 0.811 mmol) indioxane (2.0 mL) and water (0.40 mL) was purged with nitrogen to removeany oxygen. XPhos Precatalyst 2nd Generation (0.020 g, 0.027 mmol) wasadded and the reaction was purged with nitrogen and then heated at 100°C. for 16 h. The reaction mixture was concentrated and the residue waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate solution. The aqueous phase was separated and extracted withethyl acetate, and the combined organic phases were concentrated toafford an oil. This material was purified via column chromatography onsilica gel (Biotage 10 g column, gradient elution with 25-50% ethylacetate-hexane) to afford methyl(S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.132 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 497 [M+H]⁺.

Step 2. Methyl(S)-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Trifluoroacetic acid (1.0 mL, 6.49 mmol) was added to a solution of(S)-methyl6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3-chloro-4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.132 g, 0.265 mmol) in dichloromethane (1.0 mL) and the reactionmixture stirred at rt for 2 h. The reaction mixture was concentrated andthe residue was partitioned between dichloromethane and saturatedaqueous sodium bicarbonate solution. The organic phase was separated,dried over anhydrous sodium sulfate, filtered, and concentrated toafford methyl(S)-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.115 g, 88%) as an off-white solid. MS (ESI, pos. ion) m/z 396 [M+H]⁺.

Step 3. Methyl(S)-5-cyclobutoxy-2-methyl-6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

(S)-6-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.115 g, 0.290 mmol) was dissolved in methanol (3.6 mL), andformaldehyde (216 μL, 2.90 mmol) was added. The reaction was stirred for4 h at ambient temperature and was cooled to 0° C. Sodiumtriacetoxyborohydride (0.123 g, 0.58 mmol) was added, and the reactionwas slowly warmed to ambient temperature. After 16 h the reaction waspartitioned between ethyl acetate and water. The aqueous phase wasseparated and extracted with ethyl acetate, and the combined organicphases were washed with brine, and dried over anhydrous sodium sulfate,filtered, and concentrated to afford methyl(S)-5-cyclobutoxy-2-methyl-6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.115 g, 97%) as a pale orange oil. ¹H NMR (300 MHz, CDCl3) δ ppm1.16-1.33 (m, 4H), 1.33-1.41 (m, 1H), 1.41-1.54 (m, 1H), 1.55-1.68 (m,1H), 1.95-2.30 (m, 4H), 2.34-2.67 (m, 1H), 2.92 (dt, J=15.68, 6.08 Hz,1H), 3.06 (s, 2H), 3.22 (br d, J=15.54 Hz, 1H), 3.33-3.64 (m, 2H),3.69-3.89 (m, 3H), 4.33 (br s, 2H), 4.54 (dq, J=13.34, 6.69 Hz, 1H),4.78-4.97 (m, 1H), 5.32 (quin, J=7.40 Hz, 1H), 7.08-7.43 (m, 2H),7.68-7.87 (m, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 411 [M+H]+.

Example 61 Methyl(S)-5-cyclobutoxy-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-285)

Methyl(S)-5-cyclobutoxy-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from methyl(S)-6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateand tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateaccording to the procedure outlined above for Example 60. ¹H NMR (300MHz, CDCl₃) δ ppm 0.64-0.99 (m, 1H), 1.12-1.26 (m, 4H), 1.39-1.52 (m,1H), 1.55-1.67 (m, 1H), 1.97-2.14 (m, 5H), 2.14-2.27 (m, 1H), 2.30-2.58(m, 2H), 2.63 (br s, 1H), 2.73-2.78 (m, 1H), 2.79 (s, 3H), 2.84-3.09 (m,1H), 3.15 (br s, 1H), 3.37-3.63 (m, 4H), 3.64-3.92 (m, 3H), 4.54 (s,1H), 7.14-7.39 (m, 2H), 7.81 (d, J=8.21 Hz, 2H). MS (ESI, pos. ion) m/z439 [M+H]⁺.

Example 62(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-286)

Step 1. 3-methylpyridin-2-ylboronic acid

A 100-mL, 3-necked round-bottom flask was charged with2-bromo-3-methylpyridine (1.00 g, 5.81 mmol) and diethyl ether (30 mL).A solution of isopropylmagnesium chloride (2 M in THF, 8.0 mL, 16.0mmol) was added dropwise with stirring at 0° C., and the resultingsolution stirred for 3 h at 0° C. Triisopropyl borate (2.6 g, 13.8 mmol)was added, and the solution stirred for 1 h at room temperature. Thereaction was then quenched by the addition of saturated aqueous ammoniumchloride solution (10 mL). The aqueous layer was separated and extractedwith ethyl acetate (2×10 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated under vacuumto afford 3-methylpyridin-2-ylboronic acid (0.730 g, 92%) as lightyellow oil. MS (ESI, pos. ion) m/z 138 [M+H]⁺.

Step 2.(S)-1-(6-bromo-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 100-mL, round-bottom flask equipped with a balloon filled with air wascharged with(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.200 g, 0.70 mmol), pyridine (1 mL), copper (II) acetate (0.382 g,2.10 mmol), 3-methylpyridin-2-ylboronic acid 0.190 g, 1.39 mmol) andN,N-dimethylformamide (8 mL). The resulting mixture stirred at 90° C.overnight. After cooling to room temperature, the reaction mixture wasfiltered, and the filtrate was concentrated under vacuum. The residuewas purified by column chromatography on silica gel (eluting with 1:8,ethyl acetate/petroleum ether) to afford(S)-1-(6-bromo-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.129 g, 49%) as yellow oil. MS (ESI, pos. ion) m/z 375, 377 [M+H]⁺.

Step 3.(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 100-mL, round-bottom flask was charged with(S)-1-(6-bromo-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.129 g, 0.34 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.025 g,0.03 mmol), potassium carbonate (0.142 g, 1.03 mmol),1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.243 g, 1.04 mmol), 1,4-dioxane (10 mL) and water (2 mL). Theresulting mixture stirred overnight at 100° C. After cooling to roomtemperature, the reaction mixture was passed through a short pad ofCelite, and the filtrate was concentrated under vacuum. The residue waspurified by preparative thin layer chromatography (eluting with 50%ethyl acetate-petroleum ether). The product was further purified bypreparative-HPLC with the following conditions (Waters I): Column,SunFire Prep C18, 19×150 mm; mobile phase, water (0.05% ammoniumbicarbonate) and acetonitrile (54% to 80% acetonitrile in 10 min, flowrate: 20 mL/min); Detector, UV 220&254 nm. This afforded(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.0285 g, 21%) as an off-white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm1.00-1.03 (m, 4H), 1.16 (d, J=6.60 Hz, 3H), 1.32-1.42 (m, 1H), 2.20-2.28(m, 5H), 2.48 (s, 3H), 2.54-2.59 (m, 1H), 3.57-3.64 (m, 1H), 4.75-4.80(m, 1H), 6.95-7.00 (m, 1H), 7.22-7.27 (m, 1H), 7.54 (d, J=8.40 Hz, 1H),7.63 (s, 1H), 7.72-7.77 (m, 2H), 7.80 (s, 1H). MS (ESI, pos. ion) m/z403 [M+H]⁺.

The following examples were made according to the procedure outlined forExample 62:

(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(5-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-287)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.01-1.04 (m, 4H), 1.16 (d, J=6.60 Hz,3H), 1.30-1.40 (m, 1H), 2.06-2.27 (m, 8H), 2.63-2.68 (m, 1H), 3.57-3.62(m, 1H), 4.80 (m, 1H), 6.80 (d, J=8.40 Hz, 1H), 7.31-7.32 (m, 1H),7.56-7.66 (m, 2H), 7.74 (s, 1H), 7.88-7.92 (m, 2H). MS (ESI, pos. ion)m/z 403 [M+H]⁺.

(S)-1-(5-(5-chloropyridin-2-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-288)

¹H NMR (300 MHz, CD₃OD) 0.90-1.02 (m, 4H), 1.14 (d, J=6.30 Hz, 3H), 1.42(br s, 1H), 2.10-2.32 (m, 5H), 2.55-2.69 (m, 1H), 3.52-3.69 (m, 1H),4.65-4.90 (m, 1H), 7.00 (d, J=8.70 Hz, 1H), 7.30 (br s, 1H), 7.53 (d,J=8.70 Hz, 1H), 7.70 (s, 1H), 7.75-7.85 (m, 1H), 7.90 (s, 1H), 8.00 (d,J=2.70 Hz, 1H). MS (ESI, pos. ion) m/z 423[M+H]⁺.

Example 63(S)-1-(5-(7H-purin-2-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-289)

Step 1. 2-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-purine

A 100-mL, round-bottom flask was charged with 2-chloro-7H-purine (0.200g, 1.29 mmol), toluene (20 mL), p-toluene sulfonic acid (0.011 g, 0.06mmol), 3,4-dihydro-2H-pyran (0.328 g, 3.90 mmol), and the resultingsolution stirred for 2 h at 80° C. After cooling to room temperature,the reaction mixture was concentrated under vacuum. The residue waspurified by column chromatography on silica gel (eluting 1:5, with ethylacetate/petroleum ether) to afford2-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-purine (0.245 g, 79%) as brownoil. MS (ESI, pos. ion) m/z 239[M+H]⁺.

Step 2.1-((S)-6-bromo-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 100-mL, round-bottom flask was charged with(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.170 g, 0.60 mmol), 2-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-purine(0.200 g, 0.84 mmol), potassium carbonate (0.247 g, 1.79 mmol) andN,N-dimethylformamide (6 mL). The resulting mixture stirred overnight at110° C. After cooling to room temperature, the reaction mixture wasfiltered, and the filtrate was concentrated under vacuum. The residuewas purified by preparative thin layer chromatography (eluting with 1:1,ethyl acetate/petroleum ether) to afford1-((S)-6-bromo-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.200 g, 69%) as yellow oil. MS (ESI, pos. ion) m/z 486, 488[M+H]⁺.

Step 3.1-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 100-mL, round-bottom flask was charged with1-((S)-6-bromo-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.200 g, 0.41 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.030 g,0.04 mmol), potassium carbonate (0.170 g, 1.23 mmol),1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.288 g, 1.23 mmol), 1,4-dioxane (20 mL), and water (2 mL). Theresulting mixture stirred overnight at 100° C. After cooling to roomtemperature, the reaction mixture was passed through a short pad ofCelite, and the filtrate was concentrated under vacuum. The residue waspurified by preparative thin layer chromatography (eluting with 1:2,ethyl acetate/petroleum ether) to afford1-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.150 g, 71%) as light yellow oil. MS (ESI, pos. ion) m/z 514[M+H]⁺.

Step 4.(S)-1-(5-(7H-purin-2-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

A 100-mL, round-bottom flask was charged with1-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.150 g, 0.29 mmol), HCl (6 M aqueous solution, 3 mL) and methanol (20mL). The resulting solution stirred overnight at 40° C. After cooling toroom temperature, the pH of the reaction mixture was adjusted to 7-8with saturated aqueous sodium carbonate solution. The resulting mixturewas concentrated to remove the methanol and ethyl acetate was added. Theaqueous layer was separated and extracted with ethyl acetate (3×20 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by preparative-HPLCwith the following conditions (Waters I): Column, SunFire Prep C18,19×150 mm; mobile phase, water (0.05% ammonium bicarbonate) andacetonitrile (37% acetonitrile up to 58% in 10 min, flow rate: 20mL/min); Detector, UV 220&254 nm. This afforded(S)-1-(5-(7H-purin-2-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.030 g, 24%) as a yellow solid. ¹H NMR (300 MHz, CD₃OD) δ ppm0.86-1.00 (m, 4H), 1.16 (d, J=6.30 Hz, 3H), 1.21-1.49 (m, 1H), 2.18-2.47(m, 5H), 2.63-2.72 (m, 1H), 3.52-3.59 (m, 1H), 4.72-4.80 (m, 1H),7.19-7.30 (m, 1H), 7.56 (d, J=8.40 Hz, 1H), 7.60 (s, 1H), 7.99 (s, 1H),8.41 (s, 1H), 8.79 (s, 1H). MS (ESI, pos. ion) m/z 430[M+H]⁺.

Example 64 (2S)-methyl5-cyclobutoxy-6-(1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-290)

Step 1. (S)-methyl5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

A 100-mL round-bottom flask was charged with tert-butyl4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (250mg, 0.85 mmol), (S)-methyl6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(317 mg, 0.89 mmol), sodium carbonate (150 mg, 1.42 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (58 mg, 0.18mmol), 1,4-dioxane (10 mL), and water (2 mL). The resulting mixturestirred overnight at 100° C. in an oil bath. After cooling to roomtemperature, the reaction mixture was poured into 10 mL of water and thelayers were separated. The aqueous layer was extracted with ethylacetate (3×10 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith 5:1, ethyl acetate/petroleum ether) to afford (S)-methyl5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(200 mg, 52%) as yellow oil. MS (ESI, pos. ion) m/z 342[M+H]⁺.

Step 2. Methyl(2S)-6-(1-[1-[(tert-butoxy)carbonyl]-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

A 100-mL round-bottom flask was charged with (S)-methyl5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(200 mg, 0.59 mmol) and N,N-dimethylformamide (10 mL). Sodium hydride(47 mg, 1.96 mmol) was added and the mixture stirred at room temperaturefor 30 minutes. tert-Butyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (995 mg, 4.99 mmol) wasadded, and the resulting solution stirred overnight at 80° C. in an oilbath. After cooling to room temperature, the reaction mixture was pouredinto ethyl acetate (50 mL), washed with water (3×10 mL) and brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue was purified via column chromatography onsilica gel (eluting with 10:1, dichloromethane/methanol) to affordmethyl(2S)-6-(1-[1-[(tert-butoxy)carbonyl]-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(250 mg, 78%) as yellow oil. MS (ESI, pos. ion) m/z 541 [M+H]⁺.

Step 3. (2S)-methyl6-(1-(1-(tert-butoxycarbonyl)-3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A 50-mL round-bottom flask was charged with methyl(2S)-6-(1-[1-[(tert-butoxy)carbonyl]-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(250 mg, 0.46 mmol) and N,N-dimethylformamide (5 mL). Sodium hydride (78mg, 3.25 mmol) was added, and the mixture stirred at room temperaturefor 30 minutes. Methyl iodide (0.079 mL, 1.28 mmol) was added, and theresulting solution stirred for 4 h at room temperature. The reactionmixture was then poured into 20 mL of water and extracted with ethylacetate (3×20 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith 1:5, ethyl acetate/petroleum ether) to afford (2S)-methyl6-(1-(1-(tert-butoxycarbonyl)-3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(80 mg, 31%) as colorless oil. MS (ESI, pos. ion) m/z 555[M+H]⁺.

Step 4. (2S)-methyl5-cyclobutoxy-6-(1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A 25-mL round-bottom flask was charged with (2S)-methyl6-(1-(1-(tert-butoxycarbonyl)-3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(40 mg, 0.07 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1mL). The resulting solution stirred for 1 h at room temperature. Thereaction mixture was concentrated under vacuum. The residue was purifiedby Prep-HPLC with the following conditions: Column: Xbridge RP C18,19×150 mm, 5 um; Mobile Phase water (0.05% trifluoroacetic acid),acetonitrile (15% to 43% acetonitrile in 9 min, flow rate: 20 mL/min);Detector, 254/220 nm. The fractions were combined and concentrated undervacuum and the residue was further purified via reverse phasechromatography (acetonitrile/water (0.05% ammoniumbicarbonate)=5/95-95/5). The fractions were combined, concentrated andlyophilized to afford methyl(2S)-5-cyclobutoxy-6-[1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(14 mg, 43%) as an off-white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm1.10-1.20 (m, 3H), 1.25-1.50 (m, 2H), 1.50-1.70 (m, 1H), 1.95-2.52 (m,8H), 2.80-3.10 (m, 2H), 3.10-3.35 (m, 4H), 3.55-3.90 (m, 6H), 4.05-3.15(m, 1H), 4.40-4.65 (m, 2H), 7.18-7.35 (m, 2H), 7.93 (s, 1H), 8.01-8.12(m, 2H). MS (ESI, pos. ion) m/z 455[M+H]⁺.

Example 65 (2S)-methyl5-(4-fluorophenoxy)-6-(1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-291)

(2S)-methyl5-(4-fluorophenoxy)-6-(1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from methyl(S)-6-bromo-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateaccording to the procedure outlined for Example 52. ¹H NMR (400 MHz,CD₃OD) δ ppm 1.16 (d, J=6.40 Hz, 3H), 1.55-1.65 (m, 1H), 2.01-2.12 (m,1H), 2.20-2.50 (m, 3H), 2.60-2.72 (m, 1H), 2.90-3.01 (m, 3H), 3.08-3.15(m, 2H), 3.45-3.75 (m, 3H), 3.82 (s, 3H), 4.25-4.35 (m, 1H), 4.60-4.70(m, 1H), 6.65-4.75 (m, 2H), 6.90-7.00 (m, 2H), 7.50-7.60 (m, 2H),7.82-8.01 (m, 2H). MS (ESI, pos. ion) m/z 495[M+H]⁺.

Example 69 (2S)-methyl5-cyclobutoxy-6-(1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-292)

(2S)-Methyl5-cyclobutoxy-6-(1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from (2S)-methyl6-(1-(1-(tert-butoxycarbonyl)-3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateand formaldehyde according to the procedure outlined above for Example40. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.19 (d, J=6.00 Hz, 3H), 1.20-1.50 (m,2H), 1.55-1.85 (m, 1H), 2.01-2.22 (m, 4H), 2.22-2.68 (m, 4H), 2.88-3.08(m, 5H), 3.10-3.22 (m, 2H), 3.50-3.60 (m, 1H), 3.80 (s, 3H), 3.81-4.01(m, 1H), 4.05-4.25 (m, 1H), 4.30-4.45 (m, 1H), 4.48-4.70 (m, 1H),7.20-7.40 (m, 2H), 7.85-8.10 (m, 2H). MS (ESI, pos. ion) m/z 469[M+H]⁺.

Example 70 (2S)-methyl5-(4-fluorophenoxy)-6-(1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-293)

(2S)-Methyl5-(4-fluorophenoxy)-6-(1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylatewas synthesized from (2S)-methyl5-(4-fluorophenoxy)-6-(1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateand formaldehyde according to the procedure outlined above for Example40. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (d, J=6.80 Hz, 3H), 1.50-1.65 (m,1H), 1.98-2.11 (m, 1H), 2.15-2.22 (m, 1H), 2.40-2.70 (m, 3H), 2.78-3.01(m, 5H), 3.02-3.18 (m, 1H), 3.42-3.85 (m, 8H), 4.15-4.25 (m, 1H),4.55-4.72 (m, 1H), 6.72-6.80 (m, 2H), 6.90-7.01 (m, 2H), 7.50-7.62 (m,2H), 7.80-8.10 (m, 2H). MS (ESI, pos. ion) m/z 509[M+H]⁺.

Example 713-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione(I-294)

Step 1.(S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

A 100-mL round-bottom flask equipped with a balloon filled with air wascharged with(S)-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.800 g, 2.58 mmol), phenylboronic acid (0.937 g, 7.68 mmol), pyridine(0.83 mL, 10.30 mmol), dichloromethane (50 mL), and copper (II) acetate(0.934 g, 5.14 mmol). The resulting mixture stirred at 40° C. for 1 day.The mixture was cooled to room temperature and filtered. The filtratewas concentrated under vacuum, and the residue was purified via columnchromatography on silica gel (gradient elution with 5-10% ethylacetate/petroleum ether) to afford(S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.700 g, 70%) as a white solid. MS (ESI, pos. ion) m/z 386, 388[M+H]⁺.

Step 2.(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

A 100-mL round-bottom flask was charged with(S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.400 g, 1.04 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.083 g, 0.10 mmol), cesium carbonate (0.985 g,3.02 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.343 g, 1.17 mmol), 1,4-dioxane (10 mL) and water (3 mL). Theresulting mixture stirred at 100° C. overnight and was cooled to roomtemperature. The reaction mixture was passed through a short pad ofCelite, and the filtrate was concentrated under vacuum. The residue waspurified via column chromatography on silica gel (gardient elution with10-25% ethyl acetate/petroleum ether) to afford(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.200 g, 52%) as a light yellow solid. MS (ESI, pos. ion) m/z374[M+H]⁺.

Step 3.3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione

A 100-mL, round-bottom flask was charged with(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.200 g, 0.56 mmol), cesium carbonate (0.114 g, 0.35 mmol),N,N-dimethylformamide (5 mL), and 4-bromo-1λ⁶-thiane-1,1-dione (0.114 g,0.53 mmol). The resulting mixture stirred at 100° C. for 4 h and wasthen cooled to room temperature. The reaction mixture was diluted withethyl acetate (50 mL) and washed with water (3×10 mL). The organic phasewas dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue was purified via column chromatography onsilica gel (gradient elution with 25-50% ethyl acetate/petroleum). Theproduct was further purified by preparative-HPLC with the followingconditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobilephase, Water and acetonitrile (55% to 75% acetonitrile in 7 min, flowrate: 20 mL/min); Detector, UV 220&254 nm. This afforded3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione(0.122 g, 43%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.76-0.82(m, 1H), 0.92-1.02 (m, 2H), 1.13-1.22 (m, 4H), 1.42-1.50 (m, 1H),1.95-2.08 (m, 3H), 2.08-2.13 (m, 1H), 2.14-2.37 (m, 3H), 2.68-2.77 (m,1H), 3.11-3.19 (m, 2H), 3.37 (s, 1H), 3.53-3.60 (m, 1H), 4.66-4.72 (m,1H), 4.74-4.81 (m, 1H), 6.79 (d, J=8.00 Hz, 2H), 6.98 (t, J=7.60 Hz,1H), 7.23 (t, J=7.60 Hz, 2H), 7.62 (d, J=8.40 Hz, 1H), 7.83 (s, 1H),8.05 (s, 1H). MS (ESI, pos. ion) m/z 506[M+H]⁺.

The following example was made according to the procedure outlined forExample 71:

3-{4-[(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione(I-295)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.73-0.81 (m, 1H), 0.91-1.01 (m, 2H), 1.13(d, J=6.30 Hz, 4H), 1.32-147 (m, 1H), 1.94-2.15 (m, 5H), 2.16-2.34 (m,3H), 2.78-2.87 (m, 1H), 3.13-3.19 (m, 2H), 3.53-3.62 (m, 1H), 4.65-4.79(m, 2H), 6.74-6.79 (m, 2H), 6.93-7.02 (m, 2H), 7.38 (d, J=8.70 Hz, 1H),7.60 (d, J=8.40 Hz, 1H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z 524[M+H]⁺.

Example 72 (2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(2-oxopiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-296)

Step 1. tert-butyl 4-(methylsulfonyloxy)-2-oxopiperidine-1-carboxylate

A 100-mL round-bottom flask was charged with a solution of tert-butyl4-hydroxy-2-oxopiperidine-1-carboxylate (1.00 g, 4.65 mmol) indichloromethane (30 mL). Triethylamine (1.03 mL, 7.42 mmol) and4-dimethylaminopyridine (0.057 g, 0.47 mmol) were added, and the mixturewas cooled to 0° C. Methanesulfonyl chloride (0.47 mL, 6.05 mmol) wasadded dropwise and the resulting solution stirred for 1 h at roomtemperature. The reaction mixture was washed with water (2×10 mL) and0.1 M aqueous HCl solution (2×10 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum to afford tert-butyl4-(methylsulfonyloxy)-2-oxopiperidine-1-carboxylate (0.900 g, 66%) as abrown solid. MS (ESI, pos. ion) m/z 294[M+H]⁺.

Step 2. (S)-methyl5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

A 100-mL round-bottom flask was charged with tert-butyl4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.250g, 0.85 mmol), (S)-methyl6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.317 g, 0.89 mmol), sodium carbonate (0.150 g, 1.42 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.070 g, 0.085 mmol), 1,4-dioxane (10 mL), andwater (2 mL). The resulting mixture stirred overnight at 100° C., wascooled to room temperature, and water (10 mL) was added. The aqueouslayer was separated and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (eluting with 5:1, ethylacetate/petroleum ether) to afford (S)-methyl5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.200 g, 52%) as yellow oil. MS (ESI, pos. ion) m/z 342[M+H]⁺.

Step 3. (2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(2-oxopiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

An 8-mL resealable tube was charged with (S)-methyl5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.050 g, 0.15 mmol) and N,N-dimethylformamide (2 mL). Sodium hydride(60% dispersion in mineral oil, 0.012 g, 0.50 mmol) was added, and theresulting mixture stirred for 15 min at room temperature. tert-Butyl4-(methylsulfonyloxy)-2-oxopiperidine-1-carboxylate (0.141 g, 0.48 mmol)was added, and the resulting mixture stirred overnight at 50° C. Thereaction mixture was cooled to room temperature and water (10 mL) wasadded. The aqueous phase was separated and extracted with ethyl acetate(3×10 mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified by preparative-HPLC with the following conditions (Waters I):Column, Xbridge RPC18, 19×150 mm, 5 um; mobile phase, water (0.05%ammonium bicarbonate) and acetonitrile (13% to 60% acetonitrile in 8min; flow rate: 20 mL/min); Detector, UV254&220. This afforded(2S)-methyl5-cyclobutoxy-2-methyl-6-(1-(2-oxopiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.0091 mg, 14%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm1.17-1.20 (m, 3H), 1.29-1.40 (m, 1H), 1.40-1.51 (m, 1H), 1.58-1.68 (m,1H), 2.03-2.19 (m, 4H) m 2.22-2.35 (m, 3H), 2.41-2.49 (m, 1H), 2.92-2.99(m, 1H), 3.32-3.48 (m, 2H), 3.78 (s, 3H), 4.12-4.22 (m, 1H), 4.50-4.60(m, 1H), 4.78-4.88 (m, 1H), 7.25-7.33 (m, 2H), 7.87 (s, 1H), 8.05 (s,1H). MS (ESI, pos. ion) m/z 439[M+H]⁺.

The following example was made according to the procedure outlined forExample 72:

(2S)-methyl5-(4-fluorophenoxy)-2-methyl-6-(1-(2-oxopiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-297)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.17-1.20 (m, 3H), 1.54-1.62 (m, 1H),2.13-2.20 (m, 3H), 2.41-2.50 (m, 1H), 2.60-2.71 (m, 1H), 2.75-2.81 (m,2H), 6.72-6.79 (m, 2H), 2.92-2.99 (m, 1H), 3.32-3.48 (m, 2H), 3.78 (s,3H), 4.62-4.75 (m, 1H), 6.72-6.79 (m, 2H), 6.95-7.02 (m, 2H), 7.52-7.61(m, 2H), 7.81 (s, 1H), 7.94 (s, 1H). MS (ESI, pos. ion) m/z 479[M+H]⁺.

Example 73 methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-298)

Step 1. 2-(bromomethyl)-3-methyloxirane

A 2000-mL round-bottom flask was charged with (E)-1-bromobut-2-ene (50.0g, 370.4 mmol) and dichloromethane (1000 mL). 3-Chlorobenzoperoxoic acid(75 wt %, 94 g, 407 mmol) was added in portions over 1.5 h, and theresulting mixture stirred overnight at room temperature. The reactionmixture was washed with saturated aqueous sodium bicarbonate solution(3×200 mL) and brine (2×200 mL), dried over anhydrous sodium sulfate,filtered, and concentrated to afford 2-(bromomethyl)-3-methyloxirane(42.4 g, 84%) as light yellow oil. MS (ESI, pos. ion) m/z 192,194[M+H+MeCN]⁺.

Step 2. 1-benzhydryl-2-methylazetidin-3-ol

A 500-mL round-bottom flask was charged with2-(bromomethyl)-3-methyloxirane (42.4 g, 280 mmol), methanol (120 mL),and diphenylmethanamine (44 mL, 260 mmol), and the resulting solutionstirred overnight at 80° C. The reaction mixture was cooled to roomtemperature and concentrated. The residue was purified via columnchromatography on silica gel (eluting with 50:1,dichloromethane/methanol) to afford 1-benzhydryl-2-methylazetidin-3-ol(25 g, 35%) as a white solid. MS (ESI, pos. ion) m/z 254[M+H]⁺.

Step 3. 1-benzhydryl-2-methylazetidin-3-yl methanesulfonate

A 500-mL round-bottom flask was charged with1-benzhydryl-2-methylazetidin-3-ol (15.0 g, 59.2 mmol), dichloromethane(30 mL), and N,N-diisopropylamine (21 mL, 160 mmol), and the solutionwas cooled to 0° C. A solution of methanesulfonyl chloride (6.2 mL, 77mmol) in dichloromethane (10 mL) was added, and the resulting solutionstirred overnight at room temperature. The reaction mixture was pouredinto 200 mL of water, and the aqueous phase was separated and extractedwith dichloromethane (2×100 mL). The combined organic layers were washedwith brine (2×100 mL), dried over anhydrous sodium sulfate, filtered,and concentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with 20:1, dichloromethane/ethylacetate). The product was further purified by re-crystallization fromhexane to afford 1-benzhydryl-2-methylazetidin-3-yl methanesulfonate(5.6 g, 29%) as a white solid. MS (ESI, pos. ion) m/z 332[M+H]⁺.

Step 4. (2S)-methyl6-(1-(1-benzhydryl-2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A 100-mL round-bottom flask was charged with (S)-methyl5-(4-fluorophenoxy)-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.300 g, 0.79 mmol) and N,N-dimethylformamide (10 mL), and the solutionwas cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 0.047g, 1.17 mmol) was added, and the resulting mixture stirred for 30 min atroom temperature. 1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate(0.286 g, 0.86 mmol) was added, and the resulting mixture stirredovernight at 50° C. The reaction mixture was cooled to room temperatureand poured into water (30 mL). The aqueous phase was separated andextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was purified via column chromatography on silica gel(eluting with 25% ethyl acetate-petroleum ether) to afford (2S)-methyl6-(1-(1-benzhydryl-2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.100 g, 21%) as yellow oil. MS (ESI, pos. ion) m/z 617[M+H]⁺.

Step 5. methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

A 50-mL round-bottom flask was charged with (2S)-methyl6-(1-(1-benzhydryl-2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.020 g, 0.03 mmol), 1,2-dichloroethane (5 mL) and 1-chloroethylchloroformate (1 mL), and the resulting solution stirred for 3 h at 80°C. The reaction mixture was cooled to room temperature and then dilutedwith ethyl acetate (20 mL). The organic phase was separated and washedwith water (10 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting 25% ethyl acetate-petroleumether). The product was further purified by preparative-HPLC with thefollowing conditions (Waters I): Column, Xbridge RP C18, 19×150 mm, 5um; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile(20% to 80% acetonitrile in 10 min; flow rate: 20 mL/min); Detector,UV254&220. This afforded methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.0021 g, 14%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm 0.75 (d,J=6.40 Hz, 3H), 0.85-0.97 (m, 1H), 1.10-1.18 (m, 3H), 1.29-1.39 (m, 3H),1.52-1.65 (m, 1H), 1.99-2.25 (m, 2H), 2.41-2.75 (m, 2H), 3.82 (s, 3H),4.05-4.17 (m, 2H), 4.26-4.35 (m, 1H), 4.62-4.73 (m, 1H), 5.16-5.23 (m,1H), 6.73-6.81 (m, 2H), 6.93-6.99 (m, 2H), 7.51-7.62 (m, 2H), 7.85 (s,1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 451 [M+H]⁺.

The following example was made according to the procedure outlined forExample 73:

methyl(2S)-5-cyclobutoxy-2-methyl-6-(1-(2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-299)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.85-0.92 (m, 1H), 1.17-1.19 (m, 6H),1.25-1.51 (m, 11H), 1.52-1.70 (m, 2H), 1.99-2.32 (m, 7H), 2.38-2.48 (m,1H), 2.90-3.01 (m, 1H), 3.77 (s, 1H), 4.14-4.19 (m, 1H), 4.49-4.68 (m,2H), 4.72-4.82 (m, 1H), 4.92-5.10 (m, 1H), 5.31-5.45 (m, 1H), 7.26-7.33(m, 2H), 8.03 (s, 2H). MS (ESI, pos. ion) m/z 411[M+H]⁺.

Example 74N-(4-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-cyclopropyl-1H-pyrazol-5-yl)methanesulfonamide(I-300)

Step 1. 1-cyclopropyl-1H-pyrazol-5-amine

A 100-mL round-bottom flask was charged with 3,3-diethoxypropanenitrile(0.600 g, 4.19 mmol), cyclopropylhydrazine di-hydrochloride (0.610 g,4.21 mmol) and ethanol (20 mL), and the resulting solution stirred for18 h at 80° C. The reaction mixture was cooled to room temperature andconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with 10:1,dichloromethane/methanol) to afford 1-cyclopropyl-1H-pyrazol-5-amine(0.206 g, 36%) as light yellow oil. MS (ESI, pos. ion) m/z 124[M+H]⁺.

Step 2. 1-cyclopropyl-4-iodo-1H-pyrazol-5-amine

A 100-mL round-bottom flask was charged with1-cyclopropyl-1H-pyrazol-5-amine (0.410 g, 3.33 mmol) andN,N-dimethylformamide (10 mL). N-Iodosuccinimide (0.820 g, 3.64 mmol)was added, and the resulting solution stirred for 18 h at roomtemperature. The reaction mixture was poured into saturated aqueoussodium bisulfite solution (50 mL) and extracted with ethyl acetate (3×20mL). The combined organic layers were washed with brine (10 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was purified via column chromatography on silica gel(eluting with 1:1, ethyl acetate/petroleum ether) to afford1-cyclopropyl-4-iodo-1H-pyrazol-5-amine (0.440 g, 48%) as light yellowoil. MS (ESI, pos. ion) m/z 250[M+H]⁺.

Step 3.((2S)-6-(5-amino-1-cyclopropyl-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

A 50-mL round-bottom flask was charged with(S)-(5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.140 g, 0.34 mmol), 1-cyclopropyl-4-iodo-1H-pyrazol-5-amine (0.071 g,0.29 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (23.2 mg, 0.03 mmol, 0.10 equiv), sodiumcarbonate (0.061 g, 0.58 mmol), 1,4-dioxane (10 mL) and water (3 mL).The resulting mixture stirred for 18 h at 80° C. and was then cooled toroom temperature. The reaction mixture was filtered through a short padof Celite, and the filtrate was concentrated under vacuum. The residuewas purified via column chromatography on silica gel (eluting with 1:5,ethyl acetate/petroleum ether) to afford((2S)-6-(5-amino-1-cyclopropyl-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.025 g (20%) as light yellow oil. MS (ESI, pos. ion) m/z 407[M+H]⁺.

Step 4.N-(4-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-cyclopropyl-1H-pyrazol-5-yl)methanesulfonamide

An 8-mL round-bottom flask was charged with((2S)-6-(5-amino-1-cyclopropyl-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.020 g, 0.05 mmol), 1,4-dioxane (1 mL) and 4 M aqueous sodiumhydroxide solution (1 mL). Methanesulfonyl chloride (0.028 g, 0.019 mL,0.24 mmol) was added, and the resulting solution stirred overnight atroom temperature. The pH of the reaction mixture was adjusted to 7 with1 N aqueous HCl solution, and the mixture was extracted with ethylacetate (3×5 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified by preparative-HPLC with the following conditions (Waters I):Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, Water (0.05%ammonium bicarbonate) and acetonitrile (20% to 80% acetonitrile in 10min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This affordedN-(4-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-cyclopropyl-1H-pyrazol-5-yl)methanesulfonamide(0.010 g, 42%) as yellow oil. ¹H NMR (300 MHz, CD₃OD) δ ppm 0.63-0.75(m, 1H), 0.80-1.00 (m, 2H), 1.00-1.18 (m, 8H), 1.25-1.34 (m, 2H),1.51-1.68 (m, 1H), 1.85-2.11 (m, 5H), 2.25-2.42 (m, 2H), 2.99-3.08 (m,1H), 3.13 (s, 3H), 3.65-3.75 (m, 1H), 3.96-4.17 (m, 1H), 4.66-4.74 (m,1H), 7.15 (d, J=8.10 Hz, 1H), 7.38 (d, J=8.40 Hz, 1H), 7.82 (s, 1H). MS(ESI, pos. ion) m/z 485[M+H]⁺.

Example 75N-(4-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-cyclopropyl-1H-pyrazol-5-yl)acetamide(I-301)

Step 1. N-(1-cyclopropyl-4-iodo-1H-pyrazol-5-yl)acetamide

A 100-mL round-bottom flask was charged with1-cyclopropyl-4-iodo-1H-pyrazol-5-amine (0.250 g, 1.00 mmol),N,N-diisopropylamine (0.52 mL, 2.99 mmol) and dichloromethane (8 mL),and the solution was cooled to 0° C. A solution of acetyl chloride(0.085 mL, 1.19 mmol) in dichloromethane (2 mL) was added dropwise, andthe resulting solution stirred for 1 h at 0° C. The reaction mixture wasconcentrated under vacuum, and the residue was purified via columnchromatography on silica gel (gradient elution with 0.5-50% ethylacetate/petroleum ether) to affordN-(1-cyclopropyl-4-iodo-1H-pyrazol-5-yl)acetamide (0.300 g, 92%) asyellow oil. MS (ESI, pos. ion) m/z 292[M+H]⁺.

Step 2.N-(4-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-cyclopropyl-1H-pyrazol-5-yl)acetamide

A 25-mL round-bottom flask was charged withN-(1-cyclopropyl-4-iodo-1H-pyrazol-5-yl)acetamide (0.067 g, 0.23 mmol),(S)-(5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.103 g, 0.25 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.019 mg, 0.02 mmol), sodium carbonate (0.048 g,0.45 mmol), 1,4-dioxane (10 mL) and water (3 mL). The resulting mixturestirred for 18 h at 80° C. and was cooled to room temperature. Thereaction mixture was filtered through a short pad of Celite, and thefiltrate was concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (gradient elution with 0.5-50% ethylacetate/petroleum ether). The product was further purified bypreparative-HPLC with the following conditions (Waters I): Column,XBridge RP C18 OBD Column, 5 um, 19×150 mm; mobile phase, water (0.03%aqueous ammonia) and acetonitrile (16% to 34% acetonitrile in 10 min,flow rate: 20 mL/min); Detector, UV254&220 nm. This resulted in 23 mg(22%) ofN-(4-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-cyclopropyl-1H-pyrazol-5-yl)acetamideas a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.68-0.80 (m, 1H),0.91-0.99 (m, 2H), 1.06-1.19 (m, 8H), 1.28-1.45 (m, 3H), 1.55-1.68 (m,1H), 1.90-2.11 (m, 8H), 2.29-2.48 (m, 2H), 2.94-3.15 (m, 1H), 3.62-3.78(m, 1H), 4.00-4.20 (m, 1H), 4.67-4.83 (m, 1H), 7.14 (d, J=8.00 Hz, 1H),7.21 (d, J=8.40 Hz, 1H), 7.83 (s, 1H). MS (ESI, pos. ion) m/z 449[M+H]⁺.

Example 76 (S)-methyl5-cyclobutoxy-6-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-302)

Step 1. 3-(benzyloxy)cyclobutanol

A 100-mL round-bottom flask was charged with 3-(benzyloxy)cyclobutanone(2.00 g, 11.4 mmol), tetrahydrofuran (20 mL), and methanol (1 mL), andthe solution was cooled to 0° C. Sodium borohydride (0.475 g, 12.5 mmol)was added portionwise, and the resulting mixture stirred for 30 min atroom temperature. The reaction mixture was poured into water (30 mL),and extracted with ethyl acetate (2×30 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and concentrated toafford 3-(benzyloxy)cyclobutanol (1.83 g, 90%) as yellow oil. MS (ESI,pos. ion) m/z 179[M+H]⁺.

Step 2. 3-(benzyloxy)cyclobutyl methanesulfonate

A 100-mL round-bottom flask was charged with 3-(benzyloxy)cyclobutanol(1.83 g, 10.3 mmol), dichloromethane (20 mL) and triethylamine (2.15 mL,15.4 mmol), and the solution was cooled to 0° C. Methanesulfonylchloride (1.20 mL, 1.77 g, 15.4 mmol) was added dropwise, and theresulting solution stirred for 30 min at 0° C. The reaction mixture waspoured into water (30 mL) and extracted with dichloromethane (2×30 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated to afford 3-(benzyloxy)cyclobutylmethanesulfonate (2.60 g, 99%) as a light yellow solid. MS (ESI, pos.ion) m/z 257[M+H]⁺.

Step 3. 1-(3-(benzyloxy)cyclobutyl)-4-iodo-1H-pyrazole

A 250-mL round-bottom flask was charged with 4-iodo-1H-pyrazole (1.97 g,10.2 mmol), N,N-dimethylformamide (20 mL), 3-(benzyloxy)cyclobutylmethanesulfonate (2.60 g, 10.2 mmol) and cesium carbonate (9.75 g, 29.9mmol), and the resulting mixture stirred overnight at 80° C. Thereaction mixture was cooled to room temperature, poured into water (50mL), and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to afford1-(3-(benzyloxy)cyclobutyl)-4-iodo-1H-pyrazole (3.00 g, 83%) as yellowoil. MS (ESI, pos. ion) m/z 355[M+H]⁺.

Step 4. (S)-methyl6-(1-(3-(benzyloxy)cyclobutyl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A 25-mL round-bottom flask was charged with (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.100 g, 0.25 mmol), 1-(3-(benzyloxy)cyclobutyl)-4-iodo-1H-pyrazole(0.106 g, 0.30 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.020 g, 0.02 mmol), sodium carbonate (0.053 g,0.50 mmol), 1,4-dioxane (10 mL) and water (3 mL). The resulting mixturewas stirred overnight at 80° C., and then cooled to room temperature.The reaction mixture was diluted with ethyl acetate (20 mL), washed withwater (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (gradient elution with 1-10% ethylacetate/petroleum ether) to afford (S)-methyl6-(1-(3-(benzyloxy)cyclobutyl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.060 g, 48%) as a yellow solid. MS (ESI, pos. ion) m/z 502[M+H]⁺.

Step 5. (S)-methyl5-cyclobutoxy-6-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Palladium on carbon (10 wt %, 0.060 g) was added to a solution of(S)-methyl6-(1-(3-(benzyloxy)cyclobutyl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.060 g, 0.12 mmol) in methanol (10 mL), and the resulting mixturestirred at room temperature under an atmosphere of hydrogen for 16 h.The reaction mixture was filtered, and the filtrate was concentratedunder vacuum. The residue was purified by preparative-HPLC with thefollowing conditions (Waters I): Column, XBridge Prep Shield RP18 OBDColumn, 19×150 mm, 5 um; mobile phase, Water (0.05% ammoniumbicarbonate) and acetonitrile (30% to 50% acetonitrile in 10 min, flowrate: 20 mL/min); Detector, UV254&220 nm. This afforded (S)-methyl5-cyclobutoxy-6-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.031 g, 63%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.16 (d,J=6.30 Hz, 3H), 1.32-1.51 (m, 2H), 1.55-1.68 (m, 1H), 2.00-2.33 (m, 5H),2.33-2.58 (m, 3H), 2.76-2.84 (m, 2H), 2.93-3.01 (m, 1H), 3.77 (s, 3H),4.12-4.19 (m, 1H), 4.51-4.64 (m, 2H), 4.99-5.08 (m, 1H), 7.24-7.35 (m,2H), 7.86 (s, 1H), 8.04 (s, 1H). MS (ESI, pos. ion) m/z 412[M+H]⁺.

Example 77 methyl(S)-5-cyclobutoxy-2-methyl-6-(2-(piperidin-4-yl)-1H-imidazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-303)

Step 1. (S)-methyl6-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-imidazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.080 g, 0.20 mmol), tert-butyl4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (0.200 g, 0.61mmol), sodium carbonate (0.45 g, 0.42 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.010 g, 0.01 mmol) in 1,4-dioxane (10 mL) andwater (3 mL) was stirred at 90° C. overnight. The reaction mixture wascooled to room temperature, filtered through a short pad of Celite, andconcentrated under vacuum. The residue was purified via preparative thinlayer chromatography (eluting with 1:1, ethyl acetate/petroleum ether)to afford (S)-methyl6-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-imidazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.050 g, 48%) as a light yellow solid. MS (ESI, pos. ion) m/z525[M+H]⁺.

Step 2. methyl(S)-5-cyclobutoxy-2-methyl-6-(2-(piperidin-4-yl)-1H-imidazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

Trifluoroacetic acid (3 mL) was added to a solution of (S)-methyl6-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-imidazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.050 g, 0.09 mmol) in dichloromethane (6 mL), and the reaction mixturestirred at room temperature for 3 h. The reaction mixture wasconcentrated under vacuum, and the residue was purified viapreparative-HPLC (Waters I): Column: Waters HSS C18, 2.1×50 mm, 1.8 um;Mobile Phase water (0.05% ammonium bicarbonate) and acetonitrile (5% to95% acetonitrile in 10 min, flow rate: 20 mL/min); Detector: UV254&220nm. This afforded methyl(S)-5-cyclobutoxy-2-methyl-6-(2-(piperidin-4-yl)-1H-imidazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.0039 g, 10%) as an off-white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm1.15-1.26 (m, 2H), 1.32-1.68 (m, 3H), 1.95-2.55 (m, 8H), 2.97-3.19 (m,3H), 3.40-3.47 (m, 2H), 3.77-3.82 (m, 2H), 4.13-4.25 (m, 1H), 4.51-4.71(m, 3H), 7.28-7.47 (m, 2H), 8.55-8.61 (m, 1H). MS (ESI, pos. ion) m/z425[M+H]⁺.

The following example was made according to the procedure describedabove for Example 77:

methyl(S)-5-cyclobutoxy-2-methyl-6-(1-methyl-2-(piperidin-4-yl)-1H-imidazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-304)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.17 (d, J=6.30 Hz, 3H), 1.25-1.33 (m,1H), 1.85-1.99 (m, 8H), 2.18-2.27 (m, 1H), 2.50-2.61 (m, 1H), 2.81-2.95(m, 3H), 3.01-3.15 (m, 1H), 3.21-3.26 (m, 2H), 3.47 (s, 3H), 3.79 (s,3H), 3.93-3.99 (m, 1H), 6.86 (s, 1H), 7.08 (d, J=8.70 Hz, 1H), 7.37 (d,J=8.70 Hz, 1H). MS (ESI, pos. ion) m/z 439[M+H]⁺.

(S)-(5-cyclobutoxy-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-305)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.63-0.68 (m, 1H), 0.75-0.80 (m, 1H),0.80-0.85 (m, 1H), 0.95-1.01 (m, 1H), 1.05 (d, J=6.40 Hz, 3H), 1.22-1.35(m, 2H), 1.52-1.61 (m, 1H), 1.75-1.87 (m, 3H), 1.93-2.12 (m, 5H),2.27-2.33 (m, 2H), 2.55-2.61 (m, 2H), 2.89-2.95 (m, 1H), 3.01-3.07 (m,2H), 4.15-4.28 (m, 2H), 4.59-4.68 (m, 1H), 6.64 (s, 1H), 7.13 (d, J=8.40Hz, 1H), 7.64 (d, J=8.40 Hz, 1H), 7.79 (s, 1H). MS (ESI, pos. ion) m/z435[M+H]⁺.

((2S)-5-cyclobutoxy-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-5-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-306)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.67-0.75 (m, 1H), 0.75-0.85 (m, 1H),0.85-0.89 (m, 1H), 0.99-1.05 (m, 1H), 1.07 (d, J=6.40 Hz, 3H), 1.17-1.23(m, 1H), 1.41-1.51 (m, 2H), 1.67-1.78 (m, 3H), 1.78-1.99 (m, 6H),2.22-2.29 (m, 1H), 2.31-2.49 (m, 3H), 2.83-2.91 (m, 1H), 2.92-3.01 (m,2H), 3.85-3.96 (m, 2H), 4.86-4.78 (m, 1H), 6.24 (s, 1H), 7.11 (d, J=8.40Hz, 1H), 7.23 (d, J=8.40 Hz, 1H), 7.53 (s, 1H). MS (ESI, pos. ion) m/z435[M+H]⁺.

(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-307)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.68-0.75 (m, 1H), 0.81-0.89 (m, 1H),0.90-0.97 (m, 1H), 1.01-1.08 (m, 4H), 1.31-1.42 (m, 1H), 1.69-1.79 (m,2H), 1.81-1.98 (m, 3H), 2.05-2.15 (m, 1H), 2.21-2.32 (m, 1H), 2.51-2.60(m, 3H), 2.99-3.05 (m, 2H), 4.11-4.19 (m, 1H), 4.65-4.77 (m, 1H), 6.42(s, 1H), 6.76-6.82 (m, 2H), 6.96-7.01 (m, 1H), 7.28-7.33 (m, 2H),7.36-7.41 (m, 1H), 7.66 (s, 1H), 7.93 (m, 1H). MS (ESI, pos. ion) m/z457[M+H]⁺.

cyclopropyl((2S)-2-methyl-5-phenoxy-6-(1-(piperidin-4-yl)-1H-pyrazol-5-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-308)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.72-0.88 (m, 2H), 0.90-0.97 (m, 1H),1.01-1.08 (m, 4H), 1.45-1.51 (m, 2H), 1.55-1.62 (m, 1H), 1.77-1.95 (m,2H), 1.97-2.03 (m, 1H), 2.05-2.14 (m, 1H), 2.32-2.41 (m, 3H), 2.53-2.59(m, 1H), 2.91-2.99 (m, 2H), 3.89-3.95 (m, 1H), 4.73-4.81 (m, 1H), 6.08(s, 1H), 6.62-6.67 (m, 2H), 6.91-6.96 (m, 1H), 7.20-7.40 (m, 3H), 7.36(s, 1H), 7.47 (m, 1H). MS (ESI, pos. ion) m/z 457[M+H]⁺.

(S)-(5-cyclobutoxy-2-methyl-6-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(3929975) (I-309)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.68-0.77 (m, 1H), 0.89-0.99 (m, 2H), 1.13(d, J=6.60 Hz, 4H), 1.25-1.42 (m, 2H), 1.61-1.72 (m, 1H), 1.85-1.96 (m,1H), 2.05-2.26 (m, 9H), 2.29-2.56 (m, 2H), 2.75-2.88 (m, 2H), 3.02-3.11(m, 1H), 3.19-3.28 (m, 2H), 4.17-4.19 (m, 1H), 4.63-4.74 (m, 2H), 7.22(d, J=8.40 Hz, 1H), 7.72 (d, J=8.40 Hz, 1H), 8.05 (s, 1H). MS (ESI, pos.ion) m/z 436[M+H]⁺. Triazole regiochemistry tentatively assigned.

(S)-(5-cyclobutoxy-2-methyl-6-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-310)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.68-0.77 (m, 1H), 0.89-0.99 (m, 2H), 1.13(d, J=6.60 Hz, 4H), 1.25-1.47 (m, 2H), 1.61-1.69 (m, 1H), 1.85-1.96 (m,1H), 2.05-2.48 (m, 10H), 2.82-3.11 (m, 3H), 3.23-3.28 (m, 2H), 4.17-4.26(m, 1H), 4.70-4.81 (m, 2H), 7.25 (d, J=8.40 Hz, 1H), 7.82 (d, J=8.40 Hz,1H), 8.35 (s, 1H). MS (ESI, pos. ion) m/z 436[M+H]⁺. Triazoleregiochemistry tentatively assigned.

(S)-cyclopropyl(2-methyl-5-phenoxy-6-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-311)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.75-0.87 (m, 1H), 0.90-1.07 (m, 2H),1.12-1.23 (m, 4H), 1.31-1.49 (m, 1H), 1.95-2.40 (m, 7H), 2.69-2.83 (m,3H), 3.11-3.19 (m, 2H), 3.34 (s, 1H), 4.53-4.66 (m, 1H), 4.80-4.85 (m,1H), 6.78-6.83 (m, 2H), 6.95-7.03 (m, 1H), 7.24-7.30 (m, 2H), 7.43-7.59(m, 1H), 7.78 (s, 1H), 7.98 (d, J=8.40 Hz, 1H). MS (ESI, pos. ion) m/z458[M+H]⁺. Triazole regiochemistry tentatively assigned.

(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-312)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.73-0.83 (m, 1H), 0.90-1.05 (m, 2H),1.11-1.22 (m, 4H), 1.35-1.47 (m, 1H), 1.83-2.10 (m, 5H), 2.17-2.41 (m,2H), 2.69-2.80 (m, 3H), 3.10-3.20 (m, 2H), 4.51-4.62 (m, 1H), 4.75-4.83(m, 1H), 6.78-6.82 (m, 2H), 6.93-7.01 (m, 1H), 7.23-7.30 (m, 2H),7.45-7.51 (m, 1H), 8.04-8.09 (m, 2H). MS (ESI, pos. ion) m/z 458[M+H]⁺.Triazole regiochemistry tentatively assigned.

(S)-methyl6-(2-(azetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-313)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.13-1.21 (m, 3H), 1.23-1.41 (m, 1H),1.45-1.64 (m, 2H), 1.95-2.14 (m, 4H), 2.18-2.31 (m, 1H), 2.45-4.53 (m,1H), 2.91-3.02 (m, 1H), 3.78 (s, 3H), 4.01-4.19 (m, 5H), 4.33-4.48 (m,1H), 4.51-4.65 (m, 1H), 7.34 (d, J=8.70 Hz, 1H), 7.69 (d, J=8.40 Hz,1H), 7.76 (s, 1H). MS (ESI, pos. ion) m/z 414[M+H]⁺.

(S)-methyl-5-cyclobutoxy-6-(2-(3-hydroxyazetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-314)

¹H NMR (400 MHz, CD₃OD) δ ppm 1.08 (d, J=6.40 Hz, 3H), 1.16-1.25 (m,1H), 1.33-1.45 (m, 1H), 1.46-1.52 (m, 1H), 1.90-2.09 (m, 4H), 2.12-2.21(m, 1H), 2.35-2.42 (m, 1H), 2.83-2.92 (m, 1H), 3.68 (s, 3H), 3.76-3.78(m, 2H), 3.80-3.86 (m, 1H), 4.03-4.12 (m, 3H), 4.45-4.51 (m, 1H),7.24-7.27 (m, 1H), 7.67-7.73 (m, 2H). MS (ESI, pos. ion) m/z 430[M+H]⁺.

Example 78 (S)-methyl5-cyclobutoxy-2-methyl-6-(1-methyl-2-(piperazin-1-yl)-1H-imidazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-315)

Step 1. 1-(4-bromo-1-methyl-1H-imidazol-2-yl)piperazine

A 20-mL resealable tube was charged with2,4-dibromo-1-methyl-1H-imidazole (0.480 g, 2.00 mmol) and piperazine(3.4 g, 39.5 mmol), and the resulting mixture was stirred for 3 h at130° C. The reaction mixture was cooled to room temperature, dilutedwith dichloromethane (20 mL), washed with water (2×10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith 10:1, dichloromethane/methanol) to afford1-(4-bromo-1-methyl-1H-imidazol-2-yl)piperazine (0.300 g, 61%) as alight yellow solid. MS (ESI, pos. ion) m/z 245,247[M+H]⁺.

Step 2. (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

A 100-mL round-bottom flask was charged with (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.580 g, 1.47 mmol), 1-(4-bromo-1-methyl-1H-imidazol-2-yl)piperazine(0.300 g, 1.22 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.100 g, 0.12 mmol), sodium carbonate (0.260 g,2.45 mmol), 1,4-dioxane (9 mL) and water (3 mL). The resulting mixturestirred for 18 h at 80° C. The reaction mixture was cooled to roomtemperature, filtered through a short pad of Celite, and the filtratewas concentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with 10:1,dichloromethane/methanol). The product was further purified by Prep-HPLCwith the following conditions (Waters I): Column, XBridge Prep C18 OBDColumn, 5 um, 19×150 mm; mobile phase, water (0.03% aqueous ammonia) andacetonitrile (16.0% to 34.0% acetonitrile in 10 min, flow rate: 20mL/min); Detector, UV 220&254 nm. This afforded (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.015 g, 6%) as a light yellow solid. ¹H NMR (400 MHz, CD₃OD) δ ppm1.17 (d, J=4.80 Hz, 3H), 1.25-1.33 (m, 1H), 1.34-1.49 (m, 2H), 1.57-1.68(m, 1H), 2.03-2.28 (m, 5H), 2.39-2.49 (m, 1H), 2.93-2.99 (m, 1H),2.99-3.02 (m, 4H), 3.09-3.13 (m, 4H), 3.59 (s, 3H), 3.77 (s, 3H),4.18-4.23 (m, 1H), 4.51-4.53 (m, 1H), 7.18-7.29 (m, 2H), 7.53-7.57 (m,1H). MS (ESI, pos. ion) m/z 440[M+H]⁺.

Example 79 (S)-methyl5-cyclobutoxy-2-methyl-6-(2-(piperazin-1-yl)thiazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-316)

Step 1. tert-butyl 4-(4-bromothiazol-2-yl)piperazine-1-carboxylate

A 100-mL round-bottom flask was charged with 2,4-dibromothiazole (1.00g, 4.12 mmol), tert-butyl piperazine-1-carboxylate (0.918 g, 4.93 mmol),triethylamine (1.72 mL, 12.35 mmol) and N,N-dimethylformamide (20 mL).The resulting solution stirred for 18 h at 120° C. The reaction mixturewas cooled to room temperature, poured into water (50 mL), and extractedwith ethyl acetate (3×20 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was purified via column chromatography on silica gel(eluting with 10:1, dichloromethane/methanol) to afford tert-butyl4-(4-bromothiazol-2-yl)piperazine-1-carboxylate (0.350 g, 23%) as brownoil. MS (ESI, pos. ion) m/z 348, 350[M+H]⁺.

Step 2. (S)-methyl6-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A 50-mL round-bottom flask was charged with (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.080 g, 0.20 mmol), tert-butyl4-(4-bromothiazol-2-yl)piperazine-1-carboxylate (0.083 g, 0.24 mmol),sodium carbonate (0.042 g, 0.40 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.081 g, 0.10 mmol), 1,4-dioxane (10 mL) andwater (3 mL). The resulting mixture stirred for 4 h at 80° C. Thereaction mixture was cooled to room temperature, filtered through ashort pad of Celite, and the filtrate was concentrated under vacuum. Theresidue was purified via preparative thin layer chromatography (elutingwith 10:1, dichloromethane/methanol) to afford (S)-methyl6-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.070 g, 64%) as a light yellow solid. MS (ESI, pos. ion) m/z 543[M+H]⁺.

Step 3. (S)-methyl5-cyclobutoxy-2-methyl-6-(2-(piperazin-1-yl)thiazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

Trifluoroacetic acid (1 mL) was added to a solution of (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.070 g, 0.13 mmol) in dichloromethane (3 mL) and the resultingsolution stirred for 2 h at room temperature. The reaction solution wasconcentrated under vacuum, and the residue was purified bypreparative-HPLC with the following conditions (Waters 1): Column,SunFire Prep C18, 5 um, 19×100 mm; Mobile phase, water (0.05% ammoniumbicarbonate) and acetonitrile (55% to 75% acetonitrile in 7 min, flowrate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-methyl5-cyclobutoxy-2-methyl-6-(2-(piperazin-1-yl)thiazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.010 mg, 9%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.19(d, J=6.30 Hz, 3H), 1.20-1.45 (m, 3H), 1.45-1.52 (m, 1H), 2.03-2.21 (m,5H), 2.80-2.86 (m, 4H), 3.33-3.42 (m, 5H), 3.68 (s, 3H), 4.15-4.22 (m,1H), 4.40-4.50 (m, 1H), 7.15 (s, 1H), 7.27 (d, J=8.70 Hz, 1H), 7.67 (d,J=8.70 Hz, 1H). MS (ESI, pos. ion) m/z 443 [M+H]⁺.

Example 80 (S)-methyl5-cyclobutoxy-6-(2-(3-hydroxyazetidin-1-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-317)

Step 1. 1-(4-bromothiazol-2-yl)azetidin-3-ol

A mixture of 2,4-dibromothiazole (1.00 g, 4.12 mmol), azetidin-3-olhydrochloride (0.543 g, 4.96 mmol), and cesium carbonate (4.03 g, 12.37mmol) in acetonitrile (30 mL) was stirred for 18 h at 70° C. Thereaction mixture was cooled to room temperature and filtered. Thefiltrate was concentrated under vacuum, and the residue was purified viacolumn chromatography on silica gel (eluting with 10:1,dichloromethane/methanol) to afford 1-(4-bromothiazol-2-yl)azetidin-3-ol(0.535 g, 53%) as a light yellow solid. MS (ESI, pos. ion) m/z 235,237[M+H]⁺.

Step 2. (S)-methyl5-cyclobutoxy-6-(2-(3-hydroxyazetidin-1-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.080 g, 0.20 mmol), 1-(4-bromothiazol-2-yl)azetidin-3-ol (0.056 g,0.24 mmol), sodium carbonate (0.042 g, 0.40 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.081 g, 0.10 mmol) in 1,4-dioxane (10 mL) andwater (3 mL) was stirred for 4 h at 80° C. The reaction mixture wascooled to room temperature and filtered through a short pad of Celite.The filtrate was concentrated under vacuum, and the residue was purifiedvia column chromatography on silica gel (eluting with 2:1, ethylacetate/petroleum ether). The product was further purified bypreparative-HPLC with the following conditions (Waters I): Column,XBridge Prep C18 OBD Column, 5 um, 19×150 mm; mobile phase, water (0.03%aqueous ammonia) and acetonitrile (16.0 to 34.0% acetonitrile in 10 min,flow rate: 20 mL/min); Detector: UV 254&220 nm. This afforded (S)-methyl5-cyclobutoxy-6-(2-(3-hydroxyazetidin-1-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.030 g, 34%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (d,J=6.40 Hz, 3H), 1.32-1.41 (m, 1H), 1.42-1.54 (m, 1H), 1.55-1.67 (m, 1H),2.04-2.18 (m, 4H), 2.21-2.29 (m, 1H), 2.45-2.55 (m, 1H), 2.91-3.00 (m,1H), 3.78 (s, 3H), 3.90-3.96 (m, 2H), 4.15-4.21 (m, 1H), 4.32-4.39 (m,2H), 4.53-4.59 (m, 1H), 4.73-4.80 (m, 1H), 6.99 (s, 1H), 7.28-7.30 (m,1H), 7.53-7.55 (m, 1H). MS (ESI, pos. ion) m/z 430[M+H]⁺.

Example 81(S)-cyclopropyl(5-(2,5-difluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-318) and(S)-cyclopropyl(5-(3,4-difluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-319)

Step 1.(S)-(6-Bromo-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(6-bromo-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

(S)-(6-Bromo-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(6-bromo-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanonewere prepared from(S)-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand 1,2,4-trifluoro-5-nitrobenzene according to the procedure describedabove for(S)-(6-bromo-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(6-bromo-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(Example 52, Steps 1-3). MS (ESI, pos. ion) m/z 422,424[M+H]⁺.

Step 2.(S)-cyclopropyl(5-(3,4-difluorophenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H1)-yl)methanoneand(S)-cyclopropyl(5-(2,5-difluorophenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H1)-yl)methanone

A mixture of(S)-(6-bromo-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanoneand(S)-(6-bromo-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.100 g, 0.24 mmol), bis(pinacolato)diboron (0.600 g, 2.37 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.019 g, 0.02 mmol), and potassium acetate(0.046 mg, 0.47 mmol) in 1,4-dioxane (10 mL) was stirred overnight at80° C. The reaction mixture was cooled to room temperature, diluted withethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL),dried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was purified by preparative thin layerchromatography (eluting with 1:5, ethyl acetate/petroleum ether) toafford a mixture of(S)-cyclopropyl(5-(3,4-difluorophenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanoneand(S)-cyclopropyl(5-(2,5-difluorophenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.080 g, 72%) as yellow oil. MS (ESI, pos. ion) m/z 470[M+H]⁺.

Step 3.(S)-cyclopropyl(5-(2,5-difluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanoneand(S)-cyclopropyl(5-(3,4-difluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

A mixture of(S)-cyclopropyl(5-(3,4-difluorophenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanoneand(S)-cyclopropyl(5-(2,5-difluorophenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.080 g, 0.09 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (0.062 g, 0.38mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.021 g, 0.03 mmol), and cesium carbonate (0.167g, 0.51 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was stirredovernight at 90° C. The reaction mixture was cooled to room temperature,diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine(20 mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue was purified via column chromatography onsilica gel (eluting with 1:5, ethyl acetate/petroleum ether). Theproduct was further purified by preparative-HPLC with the followingconditions (Waters I): Column, Xbridge Prep C18 OBD column, 5 um, 19×150mm; mobile phase, Water (0.03% ammonium hydroxide) and acetonitrile (16%to 34% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV220&254 nm.

This afforded:(S)-cyclopropyl(5-(2,5-difluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.0083 g, 23%) (1-318) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm0.75-0.82 (m, 1H), 0.85-1.05 (m, 2H), 1.10-1.23 (m, 4H), 1.38-1.52 (m,1H), 1.95-2.05 (m, 1H), 2.17-2.42 (m, 2H), 2.65-2.79 (m, 1H), 4.08 (s,3H), 4.75-4.88 (m, 1H), 6.18-6.28 (m, 1H), 6.67-6.78 (m, 1H), 7.23-7.31(m, 1H), 7.54 (d, J=8.40 Hz, 1H), 8.01-8.10 (m, 2H). MS (ESI, pos. ion)m/z 425[M+H]⁺.

and

(S)-cyclopropyl(5-(3,4-difluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.0053 g, 15%) (I-319) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm0.72-0.83 (m, 1H), 0.89-1.02 (m, 2H), 1.11-1.22 (m, 4H), 1.35-1.49 (m,1H), 1.96-2.05 (m, 1H), 2.18-2.39 (m, 2H), 2.67-2.75 (m, 1H), 4.07 (s,3H), 4.75-4.88 (m, 1H), 6.51-6.62 (m, 1H), 6.78-6.89 (m, 1H), 7.13 (d,J=9.00 Hz, 1H), 7.20 (d, J=9.00 Hz, 1H), 7.51 (d, J=8.40 Hz, 1H),8.03-8.09 (m, 2H). MS (ESI, pos. ion) m/z 425[M+H]⁺.

Example 82(S)-cyclopropyl(5-(2-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-320)

Step 1.(S)-cyclopropyl(5-(2-fluorophenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

A mixture of(S)-(6-bromo-5-(2-fluorophenoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(prepared according to the procedures described for1-[(2S)-6-bromo-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one(Example 51, Steps 1-3), 0.270 g, 0.67 mmol), bis(pinacolato)diboron(3.30 g, 13.00 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (50 mg, 0.07 mmol), and potassium acetate (0.170g, 1.73 mmol) in 1,4-dioxane (10 mL) was stirred overnight at 80° C. Thereaction mixture was cooled to room temperature, diluted with ethylacetate 920 mL), washed with water (2×10 mL) and brine (10 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was purified via column chromatography on silica gel(eluting with 5-10% ethyl acetate-petroleum ether) to afford(S)-cyclopropyl(5-(2-fluorophenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.140 g, 46%) as a light yellow solid. MS (ESI, pos. ion) m/z452[M+H]⁺.

Step 2.(S)-cyclopropyl(5-(2-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

A mixture of(S)-cyclopropyl(5-(2-fluorophenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.140 g, 0.31 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (0.050 g, 0.31mmol), sodium carbonate (0.090 g, 0.85 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.010 g, 0.01 mmol) in 1,4-dioxane (10 mL) andwater (3 mL) was stirred overnight at 80° C. The reaction mixture wascooled to room temperature, filtered through a short pad of Celite, andconcentrated under vacuum. The residue was purified via preparative thinlayer chromatography (eluting with 2:1, petroleum ether-ethyl acetate).The product was further purified by preparative-HPLC with the followingconditions (Waters I): Column, XBridge C18, 19×150 mm, 5 um; MobilePhase water (0.05% ammonium bicarbonate) and acetonitrile (35% to 65%acetonitrile in 10 min, flow rate: 20 mL/min); Detector: UV254&220 nm.This afforded(S)-cyclopropyl(5-(2-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.033 g, 26%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.74-0.81(m, 1H), 0.89-1.03 (m, 2H), 1.11-1.21 (m, 4H), 1.35-1.47 (m, 1H),1.95-2.05 (m, 1H), 2.17-2.40 (m, 2H), 2.65-2.78 (m, 1H), 4.07 (s, 3H),4.75-4.81 (m, 1H), 6.40-6.49 (m, 1H), 6.89-6.97 (m, 2H), 7.21-7.27 (m,1H), 7.51 (d, J=8.40 Hz, 1H), 8.03 (s, 1H), 8.08 (d, J=8.40 Hz, 1H). MS(ESI, pos. ion) m/z 407[M+H]⁺.

The following example was made according to the procedure describedabove for Example 82:

(S)-cyclopropyl(8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(I-321)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.64-0.87 (m, 1H), 0.92-1.10 (m, 3H),1.10-1.35 (m, 4H), 1.65-1.80 (m, 1H), 2.10-2.41 (m, 2H), 2.68-2.79 (m,1H), 4.05 (s, 3H), 4.70-4.89 (m, 1H), 6.85 (d, J=8.00 Hz, 2H), 7.03 (t,J=7.60 Hz, 1H), 7.31 (t, J=8.00 Hz, 2H), 7.93-7.97 (m, 1H), 8.06 (s,1H). MS (ESI, pos. ion) m/z 407[M+H]⁺.

(S)-methyl8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-3,4-dihydroquinoline-1(2H)-carboxylate(I-322)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.60, 3 H), 1.21-1.36 (m,2H), 2.05-2.15 (m, 1H), 2.17-2.30 (m, 1H), 3.70 (s, 3H), 4.40 (d, J=6.60Hz, 3H), 4.35-4.45 (m, 1H), 6.81 (d, J=7.80 Hz, 2H), 7.01 (t, J=7.50 Hz,1H), 7.28-7.34 (m, 2H), 7.84 (d, J=11.4 Hz, 1H), 8.11 (s, 1H). MS (ESI,pos. ion) m/z 397[M+H]⁺.

(S)-1-(8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-323)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.05-1.31 (m, 4H), 2.10-2.44 (m, 5H),2.61-2.80 (m, 1H), 4.05 (s, 3H), 4.70-4.90 (m, 1H), 6.78-6.90 (m, 2H),6.95-7.10 (m, 1H), 7.25-7.40 (m, 2H), 7.90-8.10 (m, 2H). MS (ESI, pos.ion) m/z 381[M+H]⁺.

Example 83(S)-(5-cyclobutoxy-2-methyl-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-324)

A mixture of(S)-(6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.182 g, 0.50 mmol), 1H-pyrazole (0.340 g, 5.00 mmol), copper (I)iodide (0.038 g, 0.20 mmol),(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (0.57 g, 0.40 mmol), andpotassium carbonate (0.276 g, 2.00 mmol) in 1,4-dioxane (10 mL) stirredfor 18 h at 120° C. The reaction mixture was cooled to room temperatureand poured into ethyl acetate (50 mL). The mixture was washed with water(3×10 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by preparative thinlayer chromatography (eluting with 1:2, ethyl acetate/petroleum ether)to afford(S)-(5-cyclobutoxy-2-methyl-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.023 g, 13%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.63-0.72 (m, 1H), 0.77-0.91 (m, 2H), 0.99-1.10 (m, 4H), 1.15-1.19 (m,1H), 1.30-1.53 (m, 2H), 1.72-1.95 (m, 5H), 2.22-2.43 (m, 2H), 2.95-2.96(m, 1H), 3.88-3.95 (m, 1H), 4.63-4.71 (m, 1H), 6.51 (s, 1H), 7.24 (d,J=8.70 Hz, 1H), 7.41 (d, J=8.70 Hz, 1H), 7.73 (s, 1H), 8.08 (s, 1H). MS(ESI, pos. ion) m/z 352[M+H]⁺.

The following example was prepared according to the procedures describedabove for Example 83:

(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-325)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.65-0.99 (m, 3H), 0.95-1.11 (m, 4H),1.35-1.50 (m, 1H), 1.85-2.00 (m, 1H), 2.02-2.15 (m, 1H), 2.23-2.42 (m,1H), 2.50-2.65 (m, 1H), 4.65-4.75 (m, 1H), 6.31-6.35 (m, 1H), 6.71-6.78(m, 2H), 6.90-7.01 (m, 1H), 7.18-7.30 (m, 2H), 7.45-7.50 (m, 1H),7.58-7.68 (m, 2H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z 374 [M+H]⁺.

Example 84(S)-(5-cyclobutoxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-326)

Step 1.(S)-cyclopropyl(5-hydroxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

A mixture of(S)-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(1.20 g, 3.87 mmol), 2H-1,2,3-triazole (0.258 g, 3.74 mmol), copper (I)iodide (0.030 g, 0.16 mmol),(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (0.044 g, 0.31 mmol), andpotassium carbonate (1.60 g, 11.61 mmol) in N,N-dimethylformamide (20mL) stirred for 24 h at 120° C. The reaction mixture was cooled to roomtemperature and poured into ethyl acetate (100 mL). The mixture waswashed with water (3×20 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified bycolumn chromatography on silica gel (eluting with 1:3, ethylacetate/petroleum ether) to afford(S)-cyclopropyl(5-hydroxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.150 g, 13%) as light yellow oil. MS (ESI, pos. ion) m/z 299[M+H]⁺.

Step 2.(S)-(5-cyclobutoxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

A mixture of(S)-cyclopropyl(5-hydroxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.055 g, 0.18 mmol), bromocyclobutane (0.050 g, 0.37 mmol), and cesiumcarbonate (0.150 g, 0.46 mmol) in acetonitrile (5 mL) stirred for 18 hat 80° C. The reaction mixture was cooled to room temperature andfiltered, and the filtrate was concentrated under vacuum. The residuewas purified by preparative-HPLC with the following conditions (Waters1): Column, XBridge Prep C18 OBD Column, 5 um, 19×150 mm; mobile phase,water (0.03% aqueous ammonia) and acetonitrile (16% to 34% acetonitrilein 10 min, flow rate: 20 mL/min); Detector: UV 220&254 nm. This afforded(S)-(5-cyclobutoxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.030 g, 45%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm 0.67-0.75(m, 1H), 0.85-0.95 (m, 2H), 1.11-1.17 (m, 4H), 1.22-1.55 (m, 3H),1.74-2.01 (m, 5H), 2.31-2.46 (m, 2H), 2.95-3.07 (m, 1H), 3.88-3.94 (m,1H), 4.72-4.82 (m, 1H), 7.28 (d, J=8.40 Hz, 1H), 7.37 (d, J=8.40 Hz,1H), 7.99 (s, 2H). MS (ESI, pos. ion) m/z 353 [M+H]⁺.

Example 85(S)-cyclopropyl(2-methyl-5-phenoxy-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-327)

A 50-mL round-bottom flask equipped with balloon of air was charged with(S)-cyclopropyl(5-hydroxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.150 g, 0.50 mmol), phenylboronic acid (0.185 g, 1.52 mmol), copper(II) acetate (0.228 g, 1.26 mmol), pyridine (0.12 mL, 1.49 mmol),triethyl amine (0.10 mL, 0.75 mmol), and dichloromethane (4 mL), and theresulting mixture stirred for 18 h at 40° C. The reaction mixture wascooled to room temperature and filtered, and the filtrate wasconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with 5% dichloromethane/methanol).The product was further purified by preparative-HPLC with the followingconditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; Mobilephase, water (0.05% ammonium bicarbonate) and acetonitrile (55% to 75%acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220&254 nm.This afforded(S)-cyclopropyl(2-methyl-5-phenoxy-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.025 g, 14%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ ppm 0.76-0.84(m, 1H), 0.91-1.06 (m, 2H), 1.15-1.23 (m, 4H), 1.43-1.52 (m, 1H),1.94-2.04 (m, 1H), 2.21-2.49 (m, 2H), 2.75-2.88 (m, 1H), 4.75-4.83 (m,1H), 6.65-6.74 (m, 2H), 6.92 (d, J=7.20 Hz, 1H), 7.17 (t, J=7.50 Hz,2H), 7.52 (d, J=8.70 Hz, 1H), 7.62 (d, J=8.70 Hz, 1H), 7.75 (s, 2H). MS(ESI, pos. ion) m/z 375[M+H]⁺.

Example 86(S)-(5-cyclobutoxy-2-methyl-6-(5-(piperidin-4-yl)-1H-imidazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(I-328)

Step 1. 2,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

Sodium hydride (60% dispersion in mineral oil, 0.212 g, 5.30 mmol) wasadded in portions to a 0° C. solution of 2,5-dibromo-1H-imidazole (0.600g, 2.67 mmol) in N,N-dimethylformamide (4 mL), and the resulting mixturestirred for 30 min at 0° C. A solution of 2-(trimethylsilyl)ethoxymethylchloride (0.665 g, 4.01 mmol) in N,N-dimethylformamide (0.5 mL) wasadded at 0° C., and the resulting solution stirred for an additional 2.5h at room temperature. The reaction mixture was poured into ethylacetate (20 mL), washed with brine (3×5 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified via column chromatography on silica gel (eluting with 10:1,ethyl acetate/petroleum ether) to afford2,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0.390 g,41%) as light yellow oil. MS (ESI, pos. ion) m/z 357, 355, 359[M+H]⁺.

Step 2.((S)-6-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

A mixture of(S)-(5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.200 g, 0.49 mmol),2,5-dibromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole (0.178 g,0.50 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.046 g, 0.06 mmol), and cesium carbonate (0.549g, 1.68 mmol) in water (3 mL) and 1,4-dioxane (10 mL) stirred overnightat 80° C. The reaction mixture was cooled to room temperature andfiltered through a short pad of celite, and the filtrate wasconcentrated under vacuum. The residue was purified by preparative thinlayer chromatography (eluting with 50% ethyl acetate/petroleum ether) toafford((S)-6-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.091 g, 32%) as a white solid. MS (ESI, pos. ion) m/z 560,562[M+H]⁺.

Step 3. tert-butyl4-(2-((S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of((S)-6-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.0.091 g, 0.16 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.050 g, 0.16 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.013 g, 0.02 mmol), and cesium carbonate (0.159g, 0.49 mmol) in water (3 mL) and 1,4-dioxane (10 mL) stirred overnightat 80° C. The reaction mixture was cooled to room temperature andfiltered through a short pad of celite, and the filtrate wasconcentrated under vacuum. The residue was purified by preparative thinlayer chromatography (eluting with 1:2, ethyl acetate/petroleum ether)to afford tert-butyl4-(2-((S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.094 g, 87%) as a light yellow solid. MS (ESI, pos. ion) m/z 663[M+H]⁺.

Step 4. tert-butyl4-(2-((S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)piperidine-1-carboxylate

A mixture of tert-butyl4-[2-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-5-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate(0.094 g, 0.14 mmol) and palladium on carbon (10 wt %, 0.047 g) inmethanol (4 mL) stirred under a hydrogen atmosphere at room temperaturefor 30 minutes. The reaction mixture was filtered, and the filtrate wasconcentrated under vacuum to afford tert-butyl4-(2-((S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)piperidine-1-carboxylate(0.094 g, 100%) as a light yellow solid. MS (ESI, pos. ion) m/z665[M+H]⁺.

Step 5.(S)-(5-cyclobutoxy-2-methyl-6-(5-(piperidin-4-yl)-1H-imidazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

Hydrogen chloride (gas) was bubbled into a solution of tert-butyl4-(2-((S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)piperidine-1-carboxylate (0.094 g,0.14 mmol) in dichloromethane (4 mL) and tetrahydrofuran (1 mL), and theresulting solution stirred for 1.5 h at room temperature. The reactionmixture was concentrated under vacuum, and the residue was dissolved inmethanol (5 mL). The pH of the solution was adjusted to 8 with saturatedaqueous sodium carbonate solution, and the resulting solution wasextracted with ethyl acetate (3×10 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was purified by preparative-HPLC with the followingconditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobilephase, water (0.05% ammonium bicarbonate) and acetonitrile (55% to 75%acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220&254 nm.This afforded(S)-(5-cyclobutoxy-2-methyl-6-(5-(piperidin-4-yl)-1H-imidazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.0018 g, 3%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.71-0.78(m, 1H), 0.82-0.99 (m, 2H), 1.13-1.18 (m, 4H), 1.21-1.41 (m, 5H),1.55-1.65 (m, 1H), 1.75-2.21 (m, 9H), 2.32-2.48 (m, 2H), 2.89-3.11 (m,4H), 3.31-3.34 (m, 1H), 4.16-4.21 (m, 1H), 4.70-4.81 (m, 1H), 6.97 (s,1H), 7.26 (d, J=8.40 Hz, 1H), 7.65 (d, J=8.40 Hz, 1H). MS (ESI, pos.ion) m/z 435[M+H]⁺.

The following example was prepared according to the procedures describedabove for Example 86:

(S)-cyclopropyl(2-methyl-5-phenoxy-6-(5-(piperidin-4-yl)-1H-imidazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-329)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.83 (m, 1H), 0.85-1.01 (m, 4H),1.14-1.18 (m, 3H), 1.18-1.21 (m, 1H), 1.25-1.40 (m, 2H), 1.42-1.51 (m,1H), 1.52-1.77 (m, 3H), 1.93-2.14 (m, 4H), 2.18-2.22 (m, 2H), 2.31-2.42(m, 2H), 2.72-2.89 (m, 2H), 2.89-2.99 (m, 2H), 3.20-3.31 (m, 2H), 4.75(s, 1H), 4.81-4.86 (m, 1H), 6.72-6.82 (m, 3H), 6.92-6.99 (m, 1H),7.20-7.25 (m, 2H), 7.48 (d, J=8.40 Hz, 1H), 7.83 (d, J=8.40 Hz, 1H). MS(ESI, pos. ion) m/z 457[M+H]⁺.

Example 87(S)-cyclopropyl(5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-330)

Step 1. (S)-tert-butyl4-(4-(1-(cyclopropanecarbonyl)-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of(S)-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(1.00 g, 3.24 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(2.40 g, 6.37 mmol), sodium carbonate (0.686 g, 6.47 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.263 g, 0.32 mmol), 1,4-dioxane (15 mL), andwater (5 mL) stirred overnight at 80° C. The reaction mixture was cooledto room temperature, poured into water (20 mL), and extracted with ethylacetate (3×20 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified via column chromatography on silica gel (eluting with 70% ethylacetate/petroleum ether) to afford (S)-tert-butyl4-(4-(1-(cyclopropanecarbonyl)-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.400 g, 26%) as a dark red solid. MS (ESI, pos. ion) m/z 481 [M+H]⁺.

Step 2. (S)-tert-butyl4-(4-(1-(cyclopropanecarbonyl)-5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of (S)-tert-butyl4-(4-(1-(cyclopropanecarbonyl)-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.100 g, 0.21 mmol), 4-bromo-2,6-dimethylpyridine (0.077 g, 0.42 mmol),copper (I) iodide (0.004 g, 0.02 mmol), picolinic acid (0.013 g, 0.10mmol), and potassium phosphate (0.133 g, 0.63 mmol) in DMSO (2 mL)stirred overnight at 90° C. The reaction mixture was cooled to roomtemperature, poured into water (5 mL), and extracted with ethyl acetate(3×5 mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified via column chromatography on silica gel (eluting with 1; 2,ethyl acetate/petroleum ether) to afford (S)-tert-butyl4-(4-(1-(cyclopropanecarbonyl)-5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.030 g, 25%) as yellow oil. MS (ESI, pos. ion) m/z 586[M+H]⁺.

Step 3.(S)-cyclopropyl(5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

Trifluoroacetic acid (1 mL) was added to a solution of (S)-tert-butyl4-(4-(1-(cyclopropanecarbonyl)-5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.030 g, 0.05 mmol) in dichloromethane (3 mL), and the resultingsolution stirred for 1 h at room temperature. The reaction mixture wasconcentrated under vacuum, and the residue was purified via columnchromatography on silica gel (eluting with 1:2, ethyl acetate/petroleumether). The crude product was further purified by preparative-HPLC withthe following conditions (Waters I): Column, SunFire Prep C18, 5 um,19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) andacetonitrile (65% to 85% acetonitrile in 7 min, flow rate: 20 mL/min);Detector, UV 220/254 nm. This afforded(S)-cyclopropyl(5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.003 g, 12%) as a white powder. ¹H NMR (400 MHz, CD₃OD) δ ppm0.73-0.84 (m, 1H), 0.92-1.03 (m, 2H), 1.12-1.21 (m, 4H), 1.42-1.51 (m,1H), 1.99-2.20 (m, 5H), 2.20-2.29 (m, 2H), 2.29-2.41 (m, 6H), 2.63-2.72(m, 1H), 2.95-3.04 (m, 2H), 3.31-3.41 (m, 2H), 4.35-4.45 (m, 1H),4.79-4.90 (m, 1H), 6.53 (s, 2H), 7.45 (d, J=8.40 Hz, 1H), 7.63 (d,J=8.80 Hz, 1H), 7.79 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z486[M+H]⁺.

The following examples were made according to the procedure describedabove for Example 87:

(S)-cyclopropyl(2-methyl-5-(6-methylpyridin-2-yloxy)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-331)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.62-0.71 (m, 1H), 0.80-0.90 (m, 2H),1.03-1.10 (m, 4H), 1.31-1.38 (m, 1H), 1.70-1.81 (m, 2H), 1.89-1.97 (m,3H), 2.11-2.27 (m, 2H), 2.26 (s, 3H), 2.55-2.69 (m, 3H), 3.03-3.09 (m,2H), 4.05-4.16 (m, 1H), 4.68-4.73 (m, 1H), 6.39 (d, J=8.40 Hz, 1H), 6.80(d, J=8.40 Hz, 1H), 7.28 (d, J=8.40 Hz, 1H), 7.46-7.51 (m, 2H), 7.67 (s,1H), 7.86 (s, 1H). MS (ESI, pos. ion) m/z 472[M+H]⁺.

(S)-cyclopropyl(5-(2,6-dimethylpyridin-3-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-332)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.73-0.84 (m, 1H), 0.88-1.01 (m, 2H),1.11-1.23 (m, 4H), 1.25-1.33 (m, 1H), 1.36-1.43 (m, 1H), 1.91-2.11 (m,5H), 2.19-2.37 (m, 2H), 2.40 (s, 3H), 2.53-2.71 ((m, 4H), 2.80-2.92 (m,2H), 3.22-3.27 (m, 1H), 4.28-4.37 (m, 1H), 4.76-4.85 (m, 1H), 6.58 (d,J=8.40 Hz, 1H), 6.88 (d, J=8.40 Hz, 1H), 7.38-7.41 (m, 1H), 7.55-7.61(m, 1H), 7.71 (s, 1H), 7.86 (s, 1H). MS (ESI, pos. ion) m/z 486[M+H]⁺.

(S)-methyl2-methyl-5-(6-methylpyridin-2-yloxy)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-333)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.13-1.19 (m, 3H), 1.54-1.64 (m, 1H),1.88-1.99 (m, 2H), 2.00-2.14 (m, 3H), 2.41 (s, 4H), 2.54-2.67 (m, 1H),2.69-2.79 (m, 2H), 3.14-3.22 (m, 2H), 3.82 (s, 3H), 4.18-4.41 (m, 1H),4.65-4.73 (m, 1H), 6.41 (d, J=8.10 Hz, 1H), 6.91 (d, J=7.50 Hz, 1H),7.50-7.62 (m, 3H), 7.76 (s, 1H), 7.94 (s, 1H). MS (ESI, pos. ion) m/z462[M+H]⁺.

(S)-1-(2-methyl-5-(6-methylpyridin-2-yloxy)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-334)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.09-1.21 (m, 3H), 1.35-1.51 (m, 1H),1.81-1.95 (m, 2H), 1.96-2.10 (m, 2H), 2.16-2.31 (m, 5H), 2.38 (s, 3H),2.61-2.81 (m, 3H), 3.13-3.21 (m, 2H), 4.19-4.29 (m, 1H), 4.72-4.83 (m,1H), 6.49 (d, J=8.70 Hz, 1H), 6.90 (d, J=7.20 Hz, 1H), 7.32 (br s, 1H),7.55-7.63 (m, 2H), 7.78 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z446[M+H]⁺.

(S)-methyl5-(6-methoxypyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-335)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.15 (d, J=6.60 Hz, 3H), 1.55-1.69 (m,1H), 1.75-1.91 (m, 2H), 1.95-2.15 (m, 3H), 2.40-2.79 (m, 4H), 3.07-3.18(m, 2H), 3.66 (s, 3H), 3.80 (s, 3H), 4.15-4.22 (m, 1H), 4.60-4.75 (m,1H), 6.30 (d, J=7.80 Hz, 1H), 6.38 (d, J=7.80 Hz, 1H), 7.48-7.61 (m,3H), 7.74 (s, 1H), 7.92 (s, 1H). MS (ESI, pos. ion) m/z 478[M+H]⁺.

(S)-1-(5-(6-methoxypyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-336)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.11 (d, J=6.60 Hz, 3H), 1.31-1.48 (m,1H), 1.78-1.94 (m, 2H), 1.95-2.08 (m, 2H), 2.18-2.39 (m, 2H), 2.22 (s,3H), 2.60-2.82 (m, 3H), 3.09-3.18 (m, 2H), 3.60 (s, 3H), 4.15-4.28 (m,1H), 4.70-4.88 (m, 1H), 6.36-6.42 (m, 2H), 7.18-7.34 (m, 1H), 7.55-7.65(m, 2H), 7.77 (s, 1H), 7.20 (s, 1H). MS (ESI, pos. ion) m/z 462[M+H]⁺.

Example 88(S)-cyclopropyl(2-methyl-5-phenoxy-6-(4-(piperazin-1-yl)-1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-337)

Step 1.(S)-cyclopropyl(2-methyl-6-(4-nitro-1H-pyrazol-1-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone

A 100-mL round-bottom flask equipped with a balloon filled with air wascharged with(S)-cyclopropyl(2-methyl-5-phenoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.240 g, 0.55 mmol), 4-nitro-1H-pyrazole (0.188 g, 1.66 mmol), copper(II) acetate (0.301 g, 1.66 mmol), pyridine (0.2 mL), andN,N-dimethylformamide (5 mL), and the resulting mixture stirredovernight at 90° C. The reaction mixture was cooled to room temperatureand filtered through a pad of Celite. The filtrate was concentrated, andthe residue was purified by preparative thin layer chromatography(eluting with 1:3, ethyl acetate/petroleum ether) to afford(S)-cyclopropyl(2-methyl-6-(4-nitro-1H-pyrazol-1-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(0.060 g, 26%) as yellow oil. MS (ESI, pos. ion) m/z 419[M+H]⁺.

Step 2.(S)-(6-(4-amino-1H-pyrazol-1-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

A mixture of(S)-cyclopropyl(2-methyl-6-(4-nitro-1H-pyrazol-1-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(0.060 g, 0.15 mmol), iron powder (0.040 g, 0.72 mmol), ammoniumchloride (0.023 g, 0.43 mmol), tetrahydrofuran (4 mL), ethanol (4 mL),and water (1 mL) stirred overnight at 80° C. The reaction mixture wascooled to room temperature and filtered. The filtrate was concentratedunder vacuum, and the residue was purified by preparative thin layerchromatography (eluting with 1:1, ethyl acetate/petroleum ether) toafford(S)-(6-(4-amino-1H-pyrazol-1-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.045 g, 81%) as a brown solid. MS (ESI, pos. ion) m/z 389[M+H]⁺.

Step 3.(S)-cyclopropyl(2-methyl-5-phenoxy-6-(4-(piperazin-1-yl)-1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

A mixture of(S)-(6-(4-amino-1H-pyrazol-1-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.020 g, 0.05 mmol), bis(2-bromoethyl)amine (0.020 g, 0.09 mmol),sodium iodide (0.003 g, 0.02 mmol), and cesium carbonate (0.084 g, 0.26mmol) in acetonitrile (2 mL) stirred overnight at 85° C. The reactionmixture was cooled to room temperature and filtered. The filtrate wasconcentrated under vacuum, and the residue was purified by preparativethin layer chromatography (eluting with 10% methanol/dichloromethane).The product was further purified by preparative —HPLC with the followingconditions: Column: XBridge RP C18, 19×150 mm, 5 um; Mobile Phase: water(0.05% ammonium bicarbonate) and acetonitrile (5% to 60% acetonitrile in7.0 min, flow rate: 20 mL/min); Detector: UV220&254 nm. This afforded(S)-cyclopropyl(2-methyl-5-phenoxy-6-(4-(piperazin-1-yl)-1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.0011 g, 5%) as a light yellow solid. ¹H NMR (300 MHz, CD₃OD) δ ppm0.96-0.82 (m, 1H), 0.91-1.06 (m, 2H), 1.15-1.22 (m, 3H), 1.31-1.38 (m,2H), 1.42-1.51 (m, 1H), 1.95-2.07 (m, 1H), 2.21-2.32 (m, 1H), 2.33-2.45(m, 1H), 2.73-2.92 (m, 9H), 4.55-4.65 (m, 1H), 6.71-6.79 (m, 2H),6.93-7.01 (m, 1H), 7.19-7.26 (m, 2H), 7.40 (s, 1H), 7.45-7.50 (m, 1H),7.54-7.63 (m, 2H). MS (ESI, pos. ion) m/z 458[M+H]⁺.

The following examples were made according to the procedure describedabove for Example 88:

(S)-cyclopropyl(2-methyl-6-(4-morpholino-1H-pyrazol-1-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(I-338)

¹H NMR (300 MHz, CD₃OD) δ ppm 0.74-0.86 (m, 1H), 0.89-1.03 (m, 2H),1.13-1.24 (m, 4H), 1.42-1.51 (m, 1H), 1.93-2.07 (m, 1H), 2.21-2.33 (m,1H), 2.33-2.47 (m, 1H), 2.78-2.88 (m, 5H), 3.70-3.80 (m, 4H), 4.78-4.81(m, 1H), 6.74-6.78 (m, 2H), 6.93-7.01 (m, 1H), 7.18-7.24 (m, 2H),7.40-7.51 (m, 2H), 7.55-7.63 (m, 2H). MS (ESI, pos. ion) m/z 459[M+H]⁺.

(S)-methyl2-methyl-6-(4-morpholino-1H-pyrazol-1-yl)-5-phenoxy-3,4-dihydroquinoline-1(2H)-carboxylate(I-339)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.17 (d, J=6.60 Hz, 3H), 1.55-1.64 (m,1H), 2.05-2.18 (m, 1H), 2.49-2.58 (m, 1H), 2.67-2.80 (m, 1H), 2.80-2.86(m, 4H), 3.72-3.80 (m, 4H), 3.84 (s, 3H), 4.65-4.74 (m, 1H), 6.68-6.73(m, 2H), 6.93-7.01 (m, 1H), 7.16-7.23 (m, 2H), 7.37 (s, 1H), 7.49-7.55(m, 2H), 7.65-7.71 (m, 1H). MS (ESI, pos. ion) m/z 449[M+H]⁺.

(S)-methyl2-methyl-5-phenoxy-6-(4-(piperazin-1-yl)-1H-pyrazol-1-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-340)

¹H NMR (300 MHz, CD₃OD) δ ppm 1.17 (d, J=6.30 Hz, 3H), 1.29-1.34 (m,1H), 1.56-1.65 (m, 1H), 2.05-2.13 (m, 1H), 2.50-2.59 (m, 1H), 2.65-2.78(m, 1H), 2.82-2.91 (m, 4H), 2.92-2.97 (m, 4H), 3.82 (s, 3H), 4.64-4.72(m, 1H), 6.68-6.74 (m, 2H), 6.91-6.99 (m, 1H), 7.15-7.24 (m, 2H), 7.39(s, 1H), 7.50-7.54 (m, 2H), 7.64-7.70 (m, 1H). MS (ESI, pos. ion) m/z448[M+H]⁺.

Example 89 methyl(2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ⁶-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-341)

Step 1. 1,1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonate

Triethylamine (7.80 mL, 55.9 mmol) was added to a solution of4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (3.5 g, 23.3 mmol) indichloromethane (35.0 mL). The reaction solution was cooled to 0° C. andmethanesulfonyl chloride (3.25 ml, 41.9 mmol) was added. After 10minutes, the reaction solution was warmed to room temperature andstirred for 3 h. The reaction was quenched via the addition of saturatedaqueous ammonium chloride solution (15 mL). The organic layer wasseparated and washed with saturated aqueous sodium bicarbonate solution(15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to afford an off-white solid. The solidresidue was suspended in ethyl acetate (20 mL) and filtered. Thefiltered solid was then collected and dried in vacuo affording1,1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonate (5.1 g, 95%) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.38-2.56 (m, 4H) 2.94-3.06(m, 2H) 3.10 (s, 3H) 3.23-3.39 (m, 2H) 5.03 (tt, J=4.74, 2.49 Hz, 1H)

Step 2. methyl(2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ⁶-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

A mixture of (S)-methyl5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.160 g, 0.47 mmol), 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethanesulfonate (0.320 g, 1.40 mmol) and cesium carbonate (0.457 g,1.40 mmol) in N,N-dimethylformamide (5 mL) stirred overnight at 110° C.The reaction mixture was cooled to room temperature, diluted with water(20 mL), and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by preparative thinlayer chromatography (eluting with 50% ethyl acetate/petroleum ether).The product was further purified by preparative —HPLC with the followingconditions (Waters I): Column, Xbridge RP18 5 um, 19×150 mm; Mobilephase, water (0.05% ammonium bicarbonate) and acetonitrile (40% to 80%acetonitrile in 10 min; flow rate: 20 mL/min); Detector, UV 220&254 nm.This afforded of methyl(2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ⁶-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(0.040 g, 18%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.18 (d,J=6.40 Hz, 3H), 1.29-1.31 (m, 1H), 1.47-1.49 (m, 1H), 1.60-1.62 (m, 1H),2.01-2.08 (m, 4H), 2.11-2.24 (m, 1H), 2.45-2.47 (m, 1H), 2.63-2.68 (m,4H), 2.90-2.94 (m, 1H), 3.10-3.17 (m, 2H), 3.45-3.47 (m, 2H), 3.78 (s,3H), 4.06-1.10 (m, 1H), 4.45-4.58 (m, 2H), 7.22 (d, J=8.40 Hz, 1H), 7.31(d, J=8.40 Hz, 1H), 7.81 (s, 2H). MS (ESI, pos. ion) m/z 474[M+H]⁺.

The following examples were made according to the procedure describedabove for Example 89:

4-[4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]-1λ⁶-thiane-1,1-dione(I-342)

¹H NMR (400 MHz, CD₃OD) δ ppm 0.64-0.66 (m, 1H), 0.83-0.85 (m, 1H),0.98-0.99 (m, 1H), 1.13 (d, J=6.40 Hz, 3H), 1.24-1.37 (m, 3H), 1.58-1.65(m, 1H), 1.82-1.85 (m, 1H), 2.05-2.17 (m, 4H), 2.32-2.36 (m, 2H),2.65-2.68 (m, 4H), 2.92-2.99 (m, 1H), 3.01-3.17 (m, 2H), 3.45-3.46 (m,2H), 4.11-4.15 (m, 1H), 4.50-4.58 (m, 1H), 4.75-4.77 (m, 1H), 7.14 (d,J=8.00 Hz, 1H), 7.26 (d, J=8.00 Hz, 1H), 7.85 (s, 1H), 7.96 (s, 1H). MS(ESI, pos. ion) m/z 484[M+H]⁺.

Example 90(S)-1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-6-carbonitrile(I-343)

A mixture of(S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.100 g, 0.26 mmol), tetrakis(triphenylphosphine)palladium (0) (0.30 g,0.03 mmol), and zinc cyanide (0.036 g, 0.31 mmol) inN,N-dimethylformamide (2 mL) was heated with microwave irradiation for30 min at 160° C. The reaction mixture was cooled to room temperature,poured into ethyl acetate (10 mL), washed with water (3×2 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was purified via column chromatography on silica gel(eluting with 1:8, ethyl acetate/petroleum ether) to afford(S)-1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-6-carbonitrile(0.27 g, 32%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ ppm0.74-0.82 (m, 1H), 0.90-1.10 (m, 2H), 1.10-1.18 (m, 3H), 1.28-1.39 (m,1H), 1.49-1.61 (m, 1H), 1.80-1.91 (m, 1H), 2.10-2.22 (m, 1H), 2.39-2.51(m, 1H), 2.67-2.80 (m, 1H), 4.71-4.89 (m, 1H), 6.85 (d, J=8.10 Hz, 2H),7.08 (t, J=7.50 Hz, 1H), 7.28-7.38 (m, 2H), 7.40-7.47 (m, 1H), 7.49-7.55(m, 1H). MS (ESI, pos. ion) m/z 333 [M+H]⁺.

(S)-methyl6-cyano-2-methyl-5-phenoxy-3,4-dihydroquinoline-1(2H)-carboxylate(I-344)

(S)-Methyl6-cyano-2-methyl-5-phenoxy-3,4-dihydroquinoline-1(2H)-carboxylate wassynthesized according to the procedure outlined above for(S)-1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-6-carbonitrile(Example 90). ¹H NMR (300 MHz, CD₃Cl) δ ppm 1.12 (d, J=6.60 Hz, 3H),1.52-1.70 (m, 1H), 1.88-2.10 (m, 1H), 2.42-2.72 (m, 2H), 3.84 (s, 3H),4.62-4.80 (m, 1H), 6.82 (d, J=8.10 Hz, 2H), 7.06 (t, J=7.50 Hz, 1H),7.20-7.35 (m, 2H), 7.48 (d, J=8.70 Hz, 1H), 7.75 (d, J=8.70 Hz, 1H). MS(ESI, pos. ion) m/z 323[M+H]⁺.

Example 91(S)-cyclopropyl(6-ethynyl-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(I-345)

A mixture of(S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.030 g, 0.08 mmol), tributyl(ethynyl)stannane (0.030 g, 0.09 mmol),and tetrakis(triphenylphosphine)palladium (0) (0.037 g, 0.03 mmol) inN,N-dimethylformamide (1.5 mL) stirred overnight at 120° C. The reactionmixture was cooled to room temperature, poured into ethyl acetate (15mL), washed with water (2×5 mL) and brine (5 mL), dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified via preparative thin layer chromatography (eluting with 1:5,ethyl acetate/petroleum ether). The product was further purified bypreparative-HPLC with the following conditions (Waters III): Column,Xbridge RP C18, 19×150 mm, 5 um; mobile phase, water (0.05% ammoniumbicarbonate) and acetonitrile (50% to 100% acetonitrile in 10 min, flowrate: 20 mL/min); Detector, UV 220&254 nm. This afforded(S)-cyclopropyl(6-ethynyl-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(0.004 g, 16%) as a brown semi-solid. ¹H NMR (300 MHz, CD₃OD) δ ppm0.65-0.85 (m, 1H), 0.87-1.04 (m, 2H), 1.05-1.25 (m, 4H), 1.38-1.52 (m,1H), 1.85-2.02 (m, 1H), 2.11-2.47 (m, 2H), 2.62-2.85 (m, 1H), 3.47 (m,1H), 4.75-4.82 (m, 1H), 6.79 (d, J=8.10 Hz, 2H), 6.95-7.05 (m, 1H),7.19-7.39 (m, 3H), 7.45 (d, J=8.40 Hz, 1H). MS (ESI, pos. ion) m/z332[M+H]⁺.

Example 92 (S)-methyl6-ethynyl-2-methyl-5-phenoxy-3,4-dihydroquinoline-1(2H)-carboxylate(I-346)

(S)-Methyl6-ethynyl-2-methyl-5-phenoxy-3,4-dihydroquinoline-1(2H)-carboxylate wassynthesized according to the procedure outlined above for(S)-cyclopropyl(6-ethynyl-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone(Example 91). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.06 (d, J=6.60 Hz, 3H),1.49-1.71 (m, 1H), 1.85-2.06 (m, 1H), 2.33-2.49 (m, 2H), 3.73 (s, 3H),4.07 (s, 1H), 4.54-4.60 (m, 1H), 6.76 (d, J=7.80 Hz, 2H), 7.01 (t,J=7.50 Hz, 1H), 7.45-7.21 (m, 3H), 7.57 (d, J=8.70 Hz, 1H). MS (ESI,pos. ion) m/z 322[M+H]⁺.

Example 93(S)-cyclopropyl(2-methyl-5-phenoxy-6-(prop-1-ynyl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-347)

A mixture of(S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.050 g, 0.13 mmol), RuPhos Precatalyst 3^(rd) generation((2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate) (0.011 g, 0.01 mmol), cesium fluoride (0.099 g, 0.65mmol), and tributyl(prop-1-ynyl)stannane (0.107 g, 0.32 mmol) in1,4-dioxane (4 mL) was heated with microwave irradiation for 1 h at 160°C. The reaction mixture was cooled to room temperature, passed through ashort pad of Celite and concentrated under vacuum. The residue waspurified via preparative thin layer chromatography (eluting with 1:5,ethyl acetate/petroleum ether). The product was further purified bypreparative-HPLC with the following conditions (Waters I): Column,SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammoniumbicarbonate) and acetonitrile (50% to 100% acetonitrile in 10 min, flowrate: 20 mL/min); Detector: UV 220&254 nm. This afforded(S)-cyclopropyl(2-methyl-5-phenoxy-6-(prop-1-ynyl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.011 g, 26%) as a light brown semi-solid. ¹H NMR (400 MHz, CD₃OD) δppm 0.65-0.85 (m, 1H), 1.02-0.87 (m, 2H), 1.03-1.22 (m, 4H), 1.37-1.51(m, 1H), 1.82 (s, 3H), 1.88-2.03 (m, 1H), 2.07-2.42 (m, 2H), 2.58-2.82(m, 1H), 4.85-4.72 (m, 1H), 6.78 (d, J=7.80 Hz, 2H) 7.00 (t, J=7.50 Hz,1H), 7.25-7.31 (m, 4H). MS (ESI, pos. ion) m/z 346[M+H]⁺.

Example 94(S)-cyclopropyl(2-methyl-5-phenoxy-6-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(I-348)

Step 1.(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

A mixture of(S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.300 g, 0.78 mmol), 1H-pyrazole (0.053 g, 0.78 mmol), copper (I) oxide(0.056 g, 0.39 mmol), cesium carbonate (0.508 g, 1.56 mmol) inN,N-dimethylformamide (5 mL) stirred for 18 h at 100° C. The resultingmixture was cooled to room temperature, diluted with water (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was purified via preparative thin layerchromatography (eluting with 1:10, ethyl acetate/petroleum ether) toafford(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.050 g, 17%) as a yellow solid. MS (ESI, pos. ion) m/z 374[M+H]⁺.

Step 2.(S)-(6-(4-bromo-1H-pyrazol-1-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

N-Bromosuccinimide (0.025 g, 0.15 mmol) was added to a solution of(S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.050 g, 0.13 mmol) in N,N-dimethylformamide (2 mL), and the resultingsolution stirred overnight at room temperature. The reaction mixture wasdiluted with water (5 mL) and extracted with ethyl acetate (3×10 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified viapreparative thin layer chromatography (eluting with 1:10, ethylacetate/petroleum ether) to afford(S)-(6-(4-bromo-1H-pyrazol-1-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.055 g, 91%) as yellow oil. MS (ESI, pos. ion) m/z 452,454[M+H]⁺.

Step 3. (S)-tert-butyl4-(1-(1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of(S)-(6-(4-bromo-1H-pyrazol-1-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone(0.060 g, 0.14 mmol), tert-butyl4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(0.049 g, 0.16 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.011 g, 0.01 mmol), and cesium carbonate (0.085g, 0.26 mmol) in 1,4-dioxane (8 mL) and water (2 mL) stirred overnightat 80° C. The reaction mixture was cooled to room temperature, passedthrough a short pad of Celite, and concentrated under vacuum. Theresidue was purified via preparative thin layer chromatography (elutingwith 50% ethyl acetate/petroleum ether) afforded (S)-tert-butyl4-(1-(1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.050 g, 68%) as a white solid. MS (ESI, pos. ion) m/z 555[M+H]⁺.

Step 4. (S)-tert-butyl4-(1-(1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-4-yl)piperidine-1-carboxylate

A mixture of (S)-tert-butyl4-(1-(1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.050 g, 0.09 mmol) and palladium on charcoal (10% wt %, 0.040 g) inmethanol (15 mL) stirred under an atmosphere of hydrogen for 20 min atroom temperature. The reaction mixture was filtered and concentratedunder vacuum to afford (S)-tert-butyl4-(1-(1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-4-yl)piperidine-1-carboxylate(0.048 g, 99%) as a white solid. MS (ESI, pos. ion) m/z 557[M+H]⁺.

Step 5.(S)-cyclopropyl(2-methyl-5-phenoxy-6-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl(S)-tert-butyl4-(1-(1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-4-yl)piperidine-1-carboxylate(0.048 g, 0.09 mmol) in dichloromethane (10 mL), and the resultingsolution stirred for 20 min at room temperature. The pH of the solutionwas adjusted to 8 with saturated aqueous potassium carbonate solution,and the resulting solution was extracted with dichloromethane (2×10 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified bypreparative-HPLC with the following conditions (Waters I): Column,SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammoniumbicarbonate) and acetonitrile (20% to 50% acetonitrile in 10 min, flowrate: 20 mL/min); Detector, UV 220&254 nm. This afforded(S)-cyclopropyl(2-methyl-5-phenoxy-6-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone(0.0095 g, 24%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm0.65-0.78 (m, 1H), 0.89-0.99 (m, 2H), 1.03-1.16 (m, 4H), 1.28-1.45 (m,3H), 1.61-1.82 (m, 2H), 1.83-2.02 (m, 1H), 2.18-2.22 (m, 1H), 2.24-2.38(m, 1H), 2.45-2.62 (m, 3H), 2.68-2.82 (m, 1H), 2.88-3.01 (m, 2H),4.69-4.78 (m, 1H), 6.64 (d, J=8.80 Hz, 2H), 6.84 (t, J=7.60 Hz, 1H),7.08-7.11 (m, 2H), 7.42-7.28 (m, 2H), 7.38 (d, J=8.80 Hz, 1H), 7.48 (s,1H). MS (ESI, pos. ion) m/z 457[M+H]⁺.

Example 95 (S)-methyl5-cyclobutoxy-6-(2-(3-fluoroazetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-349)

Step 1. (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

A solution of (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(0.400 g, 1.00 mmol), tert-butyl3-(4-bromothiazol-2-yl)-3-hydroxyazetidine-1-carboxylate (0.367 g, 1.10mmol), sodium carbonate (0.212 g, 2.00 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.082 g, 0.10 mmol) in 1,4-dioxane (10 mL) andwater (3 mL) stirred overnight at 80° C. The reaction mixture was cooledto room temperature, filtered through a pad of Celite, and concentratedunder vacuum. The residue was purified via column chromatography onsilica gel (eluting with 30% ethyl acetate/petroleum ether) to afford(S)-methyl6-(2-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.366 g, 69%) as a yellow solid. MS (ESI, pos. ion) m/z 530[M+H]⁺.

Step 2. (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

(Diethylamino)sulfur trifluoride (DAST) (0.152 g, 0.94 mmol) was addedto a −78° C. solution of (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.100 g, 0.19 mmol) in dichloromethane (4 mL), and the resultingsolution stirred for 2 h at −78° C. The reaction mixture was poured intosaturated aqueous sodium bicarbonate solution (20 mL) and extracted withdichloromethane (3×20 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified via preparative thin layer chromatography (elutingwith 30% ethyl acetate/petroleum ether) to afford (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.059 g, 59%) as a yellow solid. MS (ESI, pos. ion) m/z 532[M+H]⁺.

Step 3. (S)-methyl5-cyclobutoxy-6-(2-(3-fluoroazetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Trifluoroacetic acid (1 mL) was added to a solution of (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.059 g, 0.11 mmol) in dichloromethane (3 mL), and the resultingsolution stirred for 2 h at room temperature and was then concentratedunder vacuum. The residue was purified by preparative-HPLC with thefollowing conditions (Waters I): Column, XBridge C18, 19×150 mm, 5 um;Mobile phase: water (0.05% ammonium bicarbonate) and acetonitrile (5% to95% acetonitrile in 8 min; flow rate: 20 mL/min); Detector, UV 220&254nm. This afforded (S)-methyl5-cyclobutoxy-6-(2-(3-fluoroazetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.025 g, 53%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.20 (d,J=6.40 Hz, 3H), 1.31-1.40 (m, 1H), 1.45-1.55 (m, 1H), 1.55-1.66 (m, 1H),2.02-2.18 (m, 4H), 2.22-2.31 (m, 1H), 2.49-2.55 (m, 1H), 2.95-3.06 (m,1H), 3.80 (s, 3H), 4.08-4.20 (m, 3H), 4.28-4.36 (m, 2H), 4.56-4.64 (m,1H), 7.24-7.27 (m, 1H), 7.67-7.73 (m, 2H). MS (ESI, pos. ion) m/z432[M+H]⁺.

Example 96 (S)-methyl5-cyclobutoxy-6-(2-(3-methoxyazetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-350)

Step 1. (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-3-methoxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Sodium hydride (60% dispersion in mineral oil, 0.012 g, 0.30 mmol) wasadded to a solution of (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.100 g, 0.19 mmol) in N,N-dimethylformamide (2 mL), and the resultingmixture was stirred for 30 min at room temperature. Methyl iodide (0.014mL, 0.23 mmol) was added, and the resulting mixture s stirred overnightat room temperature. The reaction mixture was poured into 10 mL ofwater, extracted with 3×10 mL of ethyl acetate. The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by Prep-TLC with ethylacetate/petroleum ether (1/3). This resulted in 70 mg (68%) of(S)-methyl6-(2-(1-(tert-butoxycarbonyl)-3-methoxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateas colorless oil. MS (ESI, pos. ion) m/z 544[M+H]⁺.

Step 2. (S)-methyl5-cyclobutoxy-6-(2-(3-methoxyazetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Trifluoroacetic acid (1 mL) was added to a solution of (S)-methyl6-(2-(1-(tert-butoxycarbonyl)-3-methoxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.070 g, 0.13 mmol) in dichloromethane (3 mL), and the resultingsolution stirred for 2 h at room temperature. The reaction mixture wasconcentrated under vacuum, and the residue was purified bypreparative-HPLC with the following conditions (Waters I): Column,Xbridge C18, 5 um, 19×150 nm; Mobile phase water (0.05% ammoniumbicarbonate) and acetonitrile (25% to 65% acetonitrile in 10 min; flowrate: 20 mL/min); Detector, 220&254 nm. This afforded (S)-methyl5-cyclobutoxy-6-(2-(3-methoxyazetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(0.037 g, 65%) as an off-white solid. ¹H NMR (400 MHz, CD3OD) 1.20 (d,J=6.80 Hz, 3H), 1.25-65 (m, 3H), 1.95-2.20 (m, 4H), 2.20-2.31 (m, 1H),2.45-2.55 (m, 1H), 2.90-3.01 (m, 1H), 3.30 (s, 3H), 3.80 (s, 3H),3.92-3.98 (m, 2H), 4.10-4.22 (m, 3H), 4.55-4.62 (m, 1H), 7.36 (d, J=8.40Hz, 1H), 7.82 (d, J=8.40 Hz, 1H), 7.95 (s, 1H). MS (ESI, pos. ion) m/z444[M+H]⁺.

Example 97(S,E)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1-(prop-1-enyl)-1H-benzo[d]imidazol-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-351) and(S,Z)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1-(prop-1-enyl)-1H-benzo[d]imidazol-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(I-352)

Step 1. 1-allyl-2-bromo-1H-benzo[d]imidazole

A mixture of 2-bromo-1H-benzo[d]imidazole (0.400 g, 2.04 mmol), allylbromide (0.35 mL, 4.08 mmol), 1,4-dioxane (15 mL), and 2 M aqueoussodium hydroxide solution (15 mL, 3.00 mmol) stirred for 2 h at 100° C.The reaction mixture was cooled to room temperature and diluted withethyl acetate (50 mL). The organic phase was separated and washed withbrine (30 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified via preparative thinlayer chromatography (eluting with 20% ethyl acetate/petroleum ether) toafford 1-allyl-2-bromo-1H-benzo[d]imidazole (0.251 g, 52%) as a yellowoil. MS (ESI, pos. ion) m/z 237, 239 [M+H]⁺.

Step 2.(S)-5-(1-allyl-1H-benzo[d]imidazol-2-yloxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinoline

A mixture of(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.200 g, 0.71 mmol), 1-allyl-2-bromo-1H-benzo[d]imidazole (0.340 g,1.44 mmol), and potassium carbonate (0.293 g, 2.12 mmol) inN,N-dimethylacetamide (10 mL) was heated in the microwave for 2 h at200° C. The reaction mixture was cooled to room temperature, filtered,and concentrated under vacuum. The residue was purified via preparativethin layer chromatography (eluting with 20% ethyl acetate/petroleumether) to afford(S)-5-(1-allyl-1H-benzo[d]imidazol-2-yloxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinoline(0.115 g, 41%) of as a light yellow solid. MS (ESI, pos. ion) m/z398,400 [M+H]⁺.

Step 3.(E/Z)—(S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methy-5-((1-(prp-1-en-1-yl)-1H-benzo[d]imidazol-2-yl)oxy)-1,2,3,4-tetrahydroquinoline

A mixture of(S)-5-(1-allyl-1H-benzo[d]imidazol-2-yloxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinoline(0.115 g, 0.29 mmol),1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.269 g, 1.15 mmol), potassium carbonate (0.118 g, 0.85 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.023 g, 0.03 mmol) in 1,4-dioxane (10 mL) andwater (3 mL) stirred for 3 h at 100° C. The reaction mixture was cooledto room temperature, filtered through a short pad of Celite andconcentrated under vacuum. The residue was purified via preparative thinlayer chromatography (eluting with 1:2, ethyl acetate/petroleum ether)to afford(S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-((1-(prop-1-en-1-yl)-1H-benzo[d]imidazol-2-yl)oxy)-1,2,3,4-tetrahydroquinoline(0.106 g, 86%) as a red oil which is mixture of E and Z isomers. MS(ESI, pos. ion) m/z 426 [M+H]⁺.

Step 4. E- andZ—(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1-(prop-1-enyl)-1H-benzo[d]imidazol-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Acetyl chloride (0.035 mL, 0.49 mmol) was added dropwise to a 0° C.solution of E- andZ—(S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1-(prop-1-enyl)-1H-benzo[d]imidazol-2-yloxy)-1,2,3,4-tetrahydroquinoline(0.070 g, 0.16 mmol) and pyridine (0.029 mL, 0.36 mmol) indichloromethane (20 mL). The resulting solution was for 2 h at roomtemperature and was then concentrated under vacuum. The residue waspurified by preparative-HPLC with the following conditions (Waters I):Column, Xbridge Prep C18, 19×150 mm; mobile phase, water (0.05% ammoniumbicarbonate) and acetonitrile (37% to 56% acetonitrile in 10 min, flowrate: 20 mL/min); Detector, UV220&254 nm. This afforded(S,E)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1-(prop-1-enyl)-1H-benzo[d]imidazol-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(2.6 mg, 3%) as a light yellow solid. (I-351)¹H NMR (300 MHz, CD₃OD) δppm 0.92-1.00 (m, 4H), 1.19 (d, J=6.60 Hz, 3H), 1.51 (br s, 1H),1.71-1.80 (m, 3H), 2.15-2.30 (m, 4H), 2.31-2.45 (m, 1H), 2.67-2.81 (m,1H), 3.51-3.65 (m, 1H), 4.70-4.92 (m, 1H), 6.11-6.25 (m, 1H), 6.70-6.79(m, 1H), 7.10-7.25 (m, 3H), 7.29-7.45 (m, 2H), 7.54 (d, J=8.40 Hz, 1H),7.66 (s, 1H), 7.86 (s, 1H). MS (ESI, pos. ion) m/z 468 [M+H]⁺. E-Propenestereochemistry tentatively assigned.(S,Z)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1-(prop-1-enyl)-1H-benzo[d]imidazol-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone(2.4 mg, 3%) was also obtained as a light yellow solid. (I-352). ¹H NMR(300 MHz, CD₃OD) δ ppm 0.88-1.00 (m, 4H), 1.18 (d, J=6.60 Hz, 3H), 1.50(br s, 1H), 2.01-2.05 (m, 3H), 2.15-2.30 (m, 4H), 2.31-2.45 (m, 1H),2.65-2.82 (m, 1H), 3.48-3.62 (m, 1H), 4.72-4.92 (m, 1H), 6.25-6.42 (m,1H), 7.05-7.35 (m, 4H), 7.36-7.45 (m, 1H), 7.48-7.58 (m, 2H), 7.65 (s,1H), 7.84 (s, 1H). MS (ESI, pos. ion) m/z 468 [M+H]⁺. Z-Propenestereochemistry tentatively assigned.

Example 98(S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one(I-353)

Step 1. tert-butyl(S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate

Balloon pressured hydrogen gas was charged into a round bottom flaskcontaining a suspension of (S)-tert-butyl4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(500 mg, 1.17 mmol) and 20% palladium hydroxide on carbon (30 mg, 0.21mmol) in methanol (10 mL). The reaction was stirred under balloonpressure for 2 hours. The reaction was vented to nitrogen and filteredthrough a pad of Celite. The filtered solution was concentrated in vacuoand purified via column chromatography on silica gel (Biotage 25 gcolumn, gradient elution with 20-40% ethyl acetate-hexane) to affordtert-butyl(S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(500 mg, 100%) as a colorless oil. MS (ESI, pos. ion) m/z 432 [M+H]⁺.

Step 2.(S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

A solution of hydrogen chloride (4.0 N in 1,4-dioxane, 1.4 mL, 5.6 mmol)was added to a solution of (S)-tert-butyl4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(480 mg, 1.1 mmol) in 1,4-dioxane (3 mL). The reaction was stirred for 3hours resulting in a white precipitate. The reaction solution wasdiluted with diethyl ether (10 mL) and the precipitate was collected byfiltration. The filtrate was further washed with diethyl ether (10 mL),collected and dried in vacuo affording the hydrochloride salt of thetitle compound as a white powder. The salt was free based vianeutralization in ethyl acetate with saturated aqueous sodium carbonatesolution until a pH=7.5 was achieved. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo affording(S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one(356 mg, 97%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.96-1.06 (m, 6H), 1.11-1.26 (m, 1H), 1.38-1.61 (m, 4H), 1.66-1.89 (m,2H), 2.20 (s, 3H), 2.16-2.28 (m, 2H), 2.52 (m, 2H), 2.67-2.80 (m, 2H),2.83-2.94 (m, 1H), 2.99 (br d, J=12.02 Hz, 2H), 3.58-3.72 (m, 2H),4.40-4.63 (br d, J=6.75 Hz, 1H), 7.03 (br s, 2H). MS (ESI, pos. ion) m/z331 [M+H]⁺.

Example 99(S)-1-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-1-yl)ethan-1-one(I-354)

Acetyl chloride (6 μL, 0.08 mmol) was added to a solution of(S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(26.1 mg, 0.07 mmol) and triethylamine (0.03 mL, 0.21 mmol) indichloromethane (1.0 mL), and the reaction stirred at room temperatureovernight. The reaction solution was purified directly via columnchromatography on silica gel (Biotage 10 g column, gradient elution with10-20% methanol in ethyl acetate) to afford(S)-1-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-1-yl)ethan-1-one(19 mg, 71%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.98-1.05 (m, 6H), 1.17-1.29 (m, 1H), 1.38-1.47 (m, 1H), 1.54-1.59 (m,1H), 1.65-1.81 (m, 5H), 2.01 (s, 6H), 2.16-2.35 (m, 2H), 2.48-2.59 (m,1H), 2.71-2.78 (m, 1H), 3.01-3.03 (m, 2H), 3.55-3.76 (m, 2H), 3.90 (brd, J=14.66 Hz, 1H), 4.52 (br d, J=13.20 Hz, 1H), 7.04 (br s, 2H). MS(ESI, pos. ion) m/z 373 [M+H]⁺.

Example 100(S)-1-(2-methyl-6-(1-(methylsulfonyl)piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one(I-355)

Methanesulfonyl chloride (4 μL, 0.05 mmol) was added to a solution of(S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(17.0 mg, 0.05 mmol) and triethylamine (0.02 mL, 0.14 mmol) indichloromethane (1.0 mL), and the reaction stirred at room temperatureovernight. The reaction solution was purified directly via columnchromatography on silica gel (Biotage 10 g column, gradient elution with10-0% hexanes in ethyl acetate) to afford(S)-1-(2-methyl-6-(1-(methylsulfonyl)piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one(14 mg, 72%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.98-1.04(m, 6H), 1.19-1.26 (m, 1H), 1.58-1.81 (m, 6H), 2.02 (s, 3H), 2.17-2.30(m, 2H), 2.68-2.85 (m, 3H), 2.89 (s, 3H), 2.89-2.99 (m, 1H), 3.60-3.76(m, 4H), 4.57 (br d, J=6.45 Hz, 1H), 7.09 (br s, 2H). MS (ESI, pos. ion)m/z 409 [M+H]⁺.

Example 101(S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-N-ethylpiperidine-1-carboxamide(I-356)

Triethylamine (0.05 mL, 0.35 mmol) was added to a solution of(S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(20.0 mg, 0.06 mmol) in dichloromethane (5 mL). The reaction was cooledto 0° C. and triphosgene (6.3 mg, 0.02 mmol) dissolved indichloromethane (3 mL) was added. The reaction mixture was warmed toroom temperature and stirred for 3 hours. Pyridine (3 μL, 0.03 mmol) andethylamine (2.7 mg, 0.06 mmol) were then added in sequence and thesolution was stirred overnight. The reaction was quenched via theaddition of water (5 mL) and 1 M citric acid (1 mL). The organic layerwas collected and further washed with water (5 mL) and brine (5 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified via columnchromatography on silica gel (Biotage 10 g column, gradient elution with0-5% methanol in ethyl acetate) to afford(S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-N-ethylpiperidine-1-carboxamide(15 mg, 61%) as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.97-1.05 (m, 6H), 1.15 (t, J=7.04 Hz, 3H), 1.18-1.27 (m, 1H), 1.37-1.53(m, 2H), 1.63 (br d, J=11.73 Hz, 2H), 1.69-1.78 (m, 2H), 2.02 (s, 3H),2.15-2.30 (m, 2H), 2.63-2.79 (m, 3H), 2.90-3.07 (m, 3H), 3.60-3.75 (m,2H), 4.07 (br d, J=16.12 Hz, 2H), 4.50-4.62 (m, 1H), 6.45 (br t, J=5.42Hz, 1H), 7.03 (br s, 2H). MS (ESI, pos. ion) m/z 402 [M+H]⁺.

Example 102 methyl(S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(I-357)

Methyl chloroformate (5 μL, 0.06 mmol) was added to a solution of(S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(20 mg, 0.05 mmol) and triethylamine (0.04 mL, 0.27 mmol) indichloromethane (0.5 mL), and the reaction stirred at room temperatureovernight. The reaction was quenched via the addition of water (5 mL).The organic layer was collected and further washed with water (5 mL) andbrine (5 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified via columnchromatography on silica gel (Biotage 10 g column, gradient elution with10-20% methanol in ethyl acetate) to afford methyl(S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate(19 mg, 89%) as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.94-1.07 (m, 6H), 1.17-1.26 (m, 1H), 1.43-1.57 (m, 2H), 1.60-1.79 (m,4H), 2.01 (s, 3H), 2.16-2.31 (m, 2H), 2.68-2.91 (m, 3H), 2.95-3.03 (m,1H), 3.58 (s, 3H), 3.61-3.73 (m, 2H), 4.04-4.15 (m, 2H), 4.56 (br d,J=6.45 Hz, 1H), 7.05 (br s, 2H). MS (ESI, pos. ion) m/z 389 [M+H]⁺.

Example 103(S)-1-(6-(1-ethylpiperidin-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one(I-358)

Iodoethane (5 μl, 0.06 mmol) was added to a solution of(S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone(20 mg, 0.06 mmol) and potassium carbonate (38 mg, 0.27 mmol) in DMF(1.0 mL), and the reaction was stirred at room temperature overnight.The reaction was quenched via the addition of water (5 mL) and extractedwith ethyl acetate (2×10 mL). The organic layer was collected andfurther washed with water (5 mL) and brine (5 mL), dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue waspurified via column chromatography on silica gel (Biotage 10 g column,gradient elution with 50-80% methanol in ethyl acetate) to afford(S)-1-(6-(1-ethylpiperidin-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one(10 mg, 51%) as a light yellow oil. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.96-1.06 (m, 6H), 1.15 (t, J=7.04 Hz, 3H), 1.15-1.26 (m, 1H), 1.38-1.61(m, 4H), 1.66-1.89 (m, 2H), 2.20 (s, 3H), 2.16-2.28 (m, 2H), 2.52 (m,2H), 2.67-2.80 (m, 2H), 2.83-2.94 (m, 1H), 2.92-3.07 (m, 3H), 3.58-3.72(m, 2H), 4.40-4.63 (br d, J=6.75 Hz, 1H), 7.03 (br s, 2H). MS (ESI, pos.ion) m/z 359 [M+H]⁺.

Example 104(S)-1-(2-methyl-5-(phenylamino)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one(I-359)

Step 1. tert-butyl(S)-4-(4-(1-acetyl-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

XPhos Precatalyst 2nd Generation (0.186 g, 0.24 mmol) was added to anitrogen purged solution of(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.672 g, 2.36 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.892 g, 2.36 mmol), and potassium phosphate (2.51 g, 11.8 mmol) in1,4-dioxane (4.0 mL) and water (0.8 mL), and the reaction mixture washeated at 100° C. overnight. The crude reaction mixture was purifieddirectly via column chromatography on silica gel (Biotage 25 g column,gradient elution with 30-10% hexanes in ethyl acetate) to affordtert-butyl(S)-4-(4-(1-acetyl-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(225 mg, 21%) as a white fluffy powder. MS (ESI, pos. ion) m/z 455[M+H]⁺.

Step 2. tert-butyl(S)-4-(4-(1-acetyl-2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Triethylamine (0.07 mL, 0.54 mmol) and N,N-dimethylpyridin-4-amine (6.1mg, 0.049 mmol) were added to a solution of (S)-tert-butyl4-(4-(1-acetyl-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(225 mg, 0.495 mmol) in dichloromethane (4.5 mL). The reaction solutionwas cooled to 0° C. andN-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide(214 mg, 0.544 mmol) was added dropwise (clear solution turns a lightyellow orange color). The reaction mixture was then slowly warmed backup to room temperature and allowed to stir for 2 hours. The reactionsolution was purified directly via column chromatography on silica gel(Biotage 25 g column, gradient elution with 0-4% MeOH indichloromethane) to afford tert-butyl(S)-4-(4-(1-acetyl-2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(290 mg, 100%) as a white solid. MS (ESI, pos. ion) m/z 587 [M+H]⁺.

Step 3. tert-butyl(S)-4-(4-(1-acetyl-2-methyl-5-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

XPhos Precatalyst 2nd Generation (10.7 mg, 0.014 mmol) was added to anitrogen purged solution of (S)-tert-butyl4-(4-(1-acetyl-2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(40 mg, 0.068 mmol), aniline (7 μL, 0.075 mmol) and potassium phosphate(43.4 mg, 0.20 mmol) in 1,4-dioxane (0.5 mL), and the reaction mixturewas heated at 100° C. overnight. The crude reaction mixture was purifieddirectly via column chromatography on silica gel (Biotage 25 g column,gradient elution with 25-40% ethyl acetate in hexanes) to afford amixture of tert-butyl(S)-4-(4-(1-acetyl-2-methyl-5-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateand tert-butyl(S)-4-(4-(1-acetyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(31 mg) as a light yellow oil. MS (ESI, pos. ion) m/z 530 [M+H]⁺ and 438[M+H]⁺.

Step 4. tert-butyl(S)-4-(4-(1-acetyl-5-((tert-butoxycarbonyl)(phenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Di-tert-butyl dicarbonate (0.02 mL, 0.088 mmol) was added to a 0° C.solution containing a mixture of (S)-tert-butyl4-(4-(1-acetyl-2-methyl-5-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateand tert-butyl(S)-4-(4-(1-acetyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(31 mg, 0.059 mmol) and DMAP (7.2 mg, 0.059 mmol) in THF (1.0 mL). Thereaction mixture was warmed to room temperature and stirred for 3 hours.The reaction solution was concentrated in vacuo and the crude productwas purified directly via column chromatography on silica gel (Biotage25 g column, gradient elution with 40-50% ethyl acetate in hexanes) toafford tert-butyl(S)-4-(4-(1-acetyl-5-((tert-butoxycarbonyl)(phenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(29.5 mg, 80%) as a white solid. MS (ESI, pos. ion) m/z 630 [M+H]⁺.

Step 5.(S)-1-(6-(1-ethylpiperidin-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

Hydrogen chloride (4 N in 1,4-dioxane, 0.024 mL, 0.095 mmol) was addedto a solution of (S)-tert-butyl4-(4-(1-acetyl-5-((tert-butoxycarbonyl)(phenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(12 mg, 0.019 mmol) in dioxane (1.0 mL). The reaction solution stirredat room temperature for 1 hour resulting in a white precipitate. Thereaction solution was concentrated under a stream of nitrogen, diethylether (1 mL) was added and the product was neutralized via the additionof saturated aqueous sodium bicarbonate (1 mL). The organic layer wascollected, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to afford(S)-1-(6-(1-ethylpiperidin-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one(5.1 mg, 62%) as a light yellow waxy solid. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.03 (d, J=6.74 Hz, 3H), 1.11-1.25 (m, 2H), 1.35-1.52 (m, 1H),1.61-1.69 (m, 1H), 1.76-1.90 (m, 2H), 1.97-2.10 (m, 2H), 2.15 (s, 3H),2.19-2.30 (m, 1H), 2.36-2.44 (m, 1H), 2.91-3.01 (m, 2H), 3.98-4.16 (m,1H), 4.53-4.68 (m, 1H), 6.84-7.04 (m, 2H), 7.04-7.11 (m, 1H), 7.12-7.19(m, 1H), 7.29-7.37 (m, 3H), 7.83 (s, 1H), 8.11 (s, 1H), 10.02 (br s,1H). MS (ESI, pos. ion) m/z 430 [M+H]⁺.

Example 105 methyl(S)-5-cyclobutoxy-6-(5-fluoro-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-360)

Step 1. 1-benzyl-4-(4-bromo-1H-pyrazol-1-yl)piperidine

Benzyl bromide (0.42 mL, 3.56 mmol) and potassium carbonate (670 mg,4.85 mmol) were added to a solution of4-(4-bromo-1H-pyrazol-1-yl)piperidine (743.7 mg, 3.23 mmol) in DMF (10mL), and the reaction stirred at room temperature overnight. Thereaction was quenched with the addition of water (50 mL) and extractedwith ethyl acetate (3×50 mL). The organic extracts were combined andwashed with water (2×50 mL) and brine (30 mL), dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude productwas purified directly via column chromatography on silica gel (Biotage25 g column, gradient elution with 20-30% ethyl acetate in hexanes) toafford 1-benzyl-4-(4-bromo-1H-pyrazol-1-yl)piperidine (673 mg, 65%) as alight yellow oil. MS (ESI, pos. ion) m/z 321 [M+H]⁺.

Step 2. 1-benzyl-4-(4-bromo-5-fluoro-1H-pyrazol-1-yl)piperidine

A solution of lithium diisopropylamide (1.0 M in THF/hexanes) (1.25 mL,1.25 mmol) was slowly added to a −78° C. solution of1-benzyl-4-(4-bromo-1H-pyrazol-1-yl)piperidine (200 mg, 0.625 mmol) inTHF (2.0 mL), and the reaction was allowed to stir at −78° C. for 1hour. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (295 mg, 0.937 mmol)was added, and the reaction stirred for an additional 1 hour at −78° C.The reaction was quenched via the addition of saturated aqueous ammoniumchloride (5 mL). The reaction was warmed to room temperature andconcentrated in vacuo. Ethyl acetate (25 mL) was added, and the organicsolution was washed with water (2×10 mL) and brine (10 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The crude product was purified directly viacolumn chromatography on silica gel (Biotage 25 g column, gradientelution with 20-30% ethyl acetate in hexanes) to afford1-benzyl-4-(4-bromo-5-fluoro-1H-pyrazol-1-yl)piperidine (53 mg, 25%) asa light yellow oil. MS (ESI, pos. ion) m/z 339 [M+H]⁺.

Step 3. methyl(S)-6-(1-(1-benzylpiperidin-4-yl)-5-fluoro-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

XPhos Precatalyst 2nd Generation (6.0 mg, 0.008 mmol) was added to anitrogen purged solution of (S)-methyl5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(30.8 mg, 0.077 mmol),1-benzyl-4-(4-bromo-5-fluoro-1H-pyrazol-1-yl)piperidine (26.0 mg, 0.077mmol), and potassium phosphate (81 mg, 0.384 mmol) in 1,4-dioxane (1.00mL) and water (0.20 mL), and the reaction mixture was heated at 100° C.overnight. The crude reaction mixture was purified directly via columnchromatography on silica gel (Biotage 25 g column, gradient elution with10-20% ethyl acetate in hexanes) to afford methyl(S)-6-(1-(1-benzylpiperidin-4-yl)-5-fluoro-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(16 mg, 39%) as a white solid. MS (ESI, pos. ion) m/z 533 [M+H]⁺.

Step 4. methyl(S)-5-cyclobutoxy-6-(5-fluoro-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Balloon filled hydrogen was charged into a nitrogen purged suspension of(S)-methyl6-(1-(1-benzylpiperidin-4-yl)-5-fluoro-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(15.0 mg, 0.028 mmol) and 20% palladium hydroxide on carbon (40 mg,0.285 mmol) in methanol (10 mL). The reaction flask was backfilled withhydrogen 3 times. The reaction solution was then stirred under ahydrogen atmosphere for 2 hours. The flask was purged with nitrogen, andthe reaction mixture was filtered through of Celite and the bed ofCelite was washed with ethyl acetate (10 mL). The filtered solvent wasthen concentrated in vacuo. The crude product was added directly to aplug of silica gel and eluted with 30% ethyl acetate in methanol toafford methyl(S)-5-cyclobutoxy-6-(5-fluoro-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(7.2 mg, 58%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.09 (d, J=6.45 Hz, 3H), 1.21-1.30 (m, 2H), 1.42-1.57 (m, 1H), 1.76-1.88(m, 3H), 1.89-2.01 (m, 5H), 2.34-2.43 (m, 2H), 2.53-2.61 (m, 1H),2.71-2.85 (m, 2H), 3.03 (br d, J=12.31 Hz, 1H), 3.13-3.21 (m, 1H), 3.68(s, 3H), 3.95-4.05 (m, 1H), 4.15-4.30 (m, 1H), 4.41-4.52 (m, 1H), 7.14(d, J=8.15 Hz, 1H), 7.29 (d, J=8.79 Hz, 1H), 7.61 (s, 1H). MS (ESI, pos.ion) m/z 443 [M+H]⁺.

Example 106 methyl(S)-5-cyclobutoxy-6-(1-((3S,4R)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(I-361)

Step 1. tert-butyl(3S,4S)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

Triethylamine (0.95 mL, 6.8 mmol) was added to a 0° C. solution of(3S,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (500.0 mg,2.28 mmol) and methanesulfonyl chloride (0.27 mL, 3.4 mmol) indichloromethane (9 mL), and the resulting mixture was warmed to roomtemperature and stirred overnight. The reaction was quenched withsaturated aqueous sodium bicarbonate (10 mL). Additional dichloromethane(10 mL) was added, and the layers were separated. The organic layer waswashed with 1M aqueous citric acid (10 mL) and brine (10 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified directly via column chromatography on silica gel(Biotage 50 g column, gradient elution with 20-30% ethyl acetate inhexanes) to afford tert-butyl(3S,4S)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (629mg, 93%) as a colorless oil that solidified to a white solid uponstanding. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.46 (s, 9H), 1.73-1.87 (m, 1H),2.15-2.25 (m, 1H), 2.97-3.12 (m, 2H), 3.08 (s, 3H), 3.85-3.95 (m, 1H),4.39-4.46 (m, 1H), 4.55-4.62 (m, 1H), 4.65-4.78 (m, 1H).

Step 2. methyl(S)-6-(1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

(3S,4S)-tert-Butyl3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (96 mg, 0.322mmol) was added to a solution of (S)-methyl5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(100 mg, 0.293 mmol) and cesium carbonate (153 mg, 0.469 mmol) in DMF(1.0 mL), and the reaction mixture was heated at 100° C. for 1 hour. Thereaction solution was cooled to room temperature, diluted with water andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water (2×25 mL) and brine (25 mL), dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The crude productwas purified via column chromatography on silica gel (Biotage 25 gcolumn, gradient elution with 20-30% ethyl acetate in hexanes) to affordmethyl(S)-6-(1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(89 mg, 56%) as a colorless oil. MS (ESI, pos. ion) m/z 543 [M+H]⁺.

Step 3. methyl(S)-5-cyclobutoxy-6-(1-((3S,4R)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Hydrogen chloride (4.0 N in 1,4-dioxane, 0.23 mL, 0.931 mmol) was addedto a solution of (S)-methyl 6-(1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(101 mg, 0.186 mmol) in 1,4-dioxane (1.0 mL), and the reaction mixturestirred at room temperature for 3 h. The reaction solution wasconcentrated under a stream of nitrogen, diluted with saturated aqueoussodium bicarbonate (1 mL) and extracted with ethyl acetate (3×1 mL). Thecombined organic layers were added directly to a plug of silica gel andeluted with 30% ethyl acetate in methanol to afford methyl(S)-5-cyclobutoxy-6-(1-((3S,4R)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(38 mg, 47%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.07 (d,J=6.45 Hz, 3H), 1.19-1.39 (m, 2H), 1.47-1.58 (m, 1H), 1.96-2.18 (m, 8H),2.34-2.43 (m, 2H), 2.55-2.72 (m, 1H), 2.77-2.89 (m, 2H), 3.00-3.13 (m,1H), 3.14 (br d, J=4.98 Hz, 1H), 3.65 (s, 3H), 4.02-4.12 (m, 1H),4.37-4.49 (m, 1H), 4.78-4.94 (m, 1H), 7.21 (d, J=8.50 Hz, 1H), 7.32 (d,J=8.79 Hz, 1H), 7.83 (s, 1H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z 443[M+H]⁺.

The following example was made according to the procedure describedabove for Example 106:

methyl(2S)-5-cyclobutoxy-6-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-362)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.45 Hz, 3H), 1.19-1.39 (m,2H), 1.47-1.58 (m, 1H), 1.96-2.18 (m, 8H), 2.34-2.43 (m, 2H), 2.55-2.72(m, 1H), 2.77-2.89 (m, 2H), 3.00-3.13 (m, 1H), 3.14 (br d, J=4.98 Hz,1H), 3.65 (s, 3H), 4.02-4.12 (m, 1H), 4.31-4.49 (m, 1H), 4.72-4.94 (m,1H), 7.21 (d, J=8.50 Hz, 1H), 7.32 (d, J=8.79 Hz, 1H), 7.83 (s, 1H),8.00 (s, 1H). MS (ESI, pos. ion) m/z 443 [M+H]⁺.

methyl(2S)-5-cyclobutoxy-6-{1-[(3S,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-363)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.06 (d, J=6.45 Hz, 3H), 1.19-1.39 (m,2H), 1.47-1.58 (m, 1H), 1.89-2.18 (m, 8H), 2.34-2.43 (m, 2H), 2.55-2.72(m, 1H), 2.77-2.87 (m, 2H), 2.88-2.95 (m, 1H), 3.65 (s, 3H), 4.01-4.11(m, 1H), 4.31-4.45 (m, 1H), 4.60-4.84 (m, 1H), 7.21 (d, J=8.50 Hz, 1H),7.28 (d, J=8.79 Hz, 1H), 7.82 (s, 1H), 8.08 (s, 1H). MS (ESI, pos. ion)m/z 443 [M+H]⁺.

methyl(2S)-5-(4-fluorophenoxy)-6-{1-[(3S,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-364)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.04 (d, J=6.74 Hz, 3H), 1.51 (dd,J=13.34, 5.72 Hz, 1H), 1.79-1.98 (m, 4H), 2.34-2.46 (m, 4H), 2.87 (br d,J=9.09, 1H), 3.19-3.29 (m, 1H), 3.70 (s, 3H), 4.17-4.35 (m, 1H),4.50-4.77 (m, 2H), 6.73-6.77 (m, 2H), 7.06-7.12 (m, 2H), 7.54 (d, J=2.93Hz, 2H), 7.76 (s, 1H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z 483 [M+H]⁺.

methyl(2S)-5-(4-fluorophenoxy)-6-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-365)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.04 (d, J=6.74 Hz, 3H), 1.51 (dd,J=13.92, 4.84 Hz, 1H), 1.71-1.80 (m, 1H), 1.90-2.04 (m, 3H), 2.34-2.46(m, 4H), 2.93-3.10 (m, 1H), 3.11-3.19 (m, 1H), 3.70 (s, 3H), 4.27-4.42(m, 1H), 4.48-4.57 (m, 1H), 4.65-4.84 (m, 1H), 6.72-6.76 (m, 2H),7.06-7.12 (m, 2H), 7.51-7.61 (m, 2H), 7.76 (s, 1H), 7.94 (s, 1H). MS(ESI, pos. ion) m/z 483 [M+H]⁺.

methyl(2S)-5-(4-fluorophenoxy)-6-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-366)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.04 (d, J=6.74 Hz, 3H), 1.51 (dd,J=13.92, 4.84 Hz, 1H), 1.71-1.80 (m, 1H), 1.90-2.04 (m, 3H), 2.34-2.46(m, 4H), 2.93-3.10 (m, 1H), 3.11-3.19 (m, 1H), 3.70 (s, 3H), 4.27-4.42(m, 1H), 4.48-4.57 (m, 1H), 4.63-4.85 (m, 1H), 6.72-6.76 (m, 2H),7.06-7.12 (m, 2H), 7.51-7.61 (m, 2H), 7.76 (s, 1H), 7.94 (s, 1H). MS(ESI, pos. ion) m/z 483 [M+H]⁺.

methyl(2S)-5-cyclobutoxy-6-{1-[(3R,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-367)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.06 (d, J=6.45 Hz, 3H), 1.17-1.28 (m,1H), 1.29-1.42 (m, 1H), 1.47-1.56 (m, 1H), 1.86-2.17 (m, 8H), 2.34-2.43(m, 2H), 2.55-2.72 (m, 1H), 2.77-2.87 (m, 2H), 2.88-2.95 (m, 1H), 3.65(s, 3H), 4.01-4.11 (m, 1H), 4.31-4.45 (m, 1H), 4.60-4.84 (m, 1H), 7.21(d, J=8.50 Hz, 1H), 7.28 (d, J=8.79 Hz, 1H), 7.82 (s, 1H), 8.08 (s, 1H).MS (ESI, pos. ion) m/z 443 [M+H]⁺.

methyl(2S)-5-(4-fluorophenoxy)-6-{1-[(3R,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-368)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.04 (d, J=6.74 Hz, 3H), 1.51 (dd,J=13.92, 4.84 Hz, 1H), 1.71-1.84 (m, 2H), 1.90-2.04 (m, 3H), 2.67-2.73(m, 1H), 2.81-2.93 (m, 2H), 3.11-3.19 (m, 1H), 3.70 (s, 3H), 4.23-4.36(m, 1H), 4.50-4.60 (m, 1H), 4.63-4.83 (m, 1H), 6.72-6.76 (m, 2H),7.06-7.12 (m, 2H), 7.54 (d, J=2.93 Hz, 2H), 7.76 (s, 1H), 8.02 (s, 1H).MS (ESI, pos. ion) m/z 483 [M+H]⁺.

(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline(I-369)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.59-0.68 (m, 1H), 0.73-0.87 (m, 2H),0.91-0.98 (m, 1H), 1.01 (d, J=6.45 Hz, 3H), 1.17-1.31 (m, 2H), 1.49-1.59(m, 1H), 1.73-1.93 (m, 2H), 1.96-2.17 (m, 6H), 2.23-2.33 (m, 2H),2.60-2.77 (m, 1H), 2.86-2.95 (m, 2H), 4.05-4.18 (m, 1H), 4.29-4.39 (m,1H), 4.43-4.62 (m, 2H), 4.74-4.97 (m, 1H), 7.08 (d, J=8.50 Hz, 1H), 7.42(d, J=8.50 Hz, 1H), 7.87 (s, 1H), 8.07 (s, 1H). MS (ESI, pos. ion) m/z453 [M+H]⁺.

methyl(2S)-5-cyclobutoxy-6-{1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-370) and methyl(2S)-5-cyclobutoxy-6-{1-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate(I-371)

2:1 Mixture of isomers. Major isomer: ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.09 (d, J=6.45 Hz, 3H), 1.19-1.43 (m, 2H), 1.49-1.60 (m, 1H), 1.99-2.22(m, 4H), 2.35-2.43 (m, 1H), 2.79-3.11 (m, 4H), 3.68 (s, 3H), 4.07-4.15(m, 1H), 4.40-4.47 (m, 1H), 4.69-4.85 (m, 1H), 5.01-5.18 (m, 2H),5.26-5.37 (m, 1H), 7.23 (d, J=8.50 Hz, 1H), 7.33 (d, J=8.79 Hz, 1H),7.84 (s, 1H), 8.10 (s, 1H). MS (ESI, pos. ion) m/z 429 [M+H]⁺.

(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-[(3R,4S)-4-fluoropiperidin-3-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline(I-372) and(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-[(3S,4R)-4-fluoropiperidin-3-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline(I-373)

1:1 mixture of isomers. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.51-0.62 (m, 1H),0.73-0.83 (m, 2H), 0.87-0.95 (m, 1H), 1.06 (d, J=6.45 Hz, 3H), 1.12-1.30(m, 4H), 1.50-1.63 (m, 1H), 1.73-1.82 (m, 1H), 1.90-2.15 (m, 7H),2.23-2.33 (m, 2H), 2.88-2.98 (m, 1H), 3.05-3.32 (m, 1H), 3.41-3.62 (m,1H), 4.00-4.11 (m, 1H), 4.60-4.73 (m, 1H), 4.96-5.29 (m, 1H), 7.06 (d,J=8.21 Hz, 1H), 7.19 (m, 1H), 7.78 (s, 1H), 7.89 (s, 1H). MS (ESI, pos.ion) m/z 453 [M+H]⁺.

Example 107 methyl(S)-5-cyclobutoxy-2-methyl-6-(1-((2S,4R)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-374) and methyl(S)-5-cyclobutoxy-2-methyl-6-(1-((2R,4S)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-375)

Step 1. tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate

Di-tert-butyl dicarbonate (1.09 g, 5.01 mmol) was added to a 0° C.solution of 2-methylpiperidin-4-one hydrochloride (1:1 mixture ofisomers, 0.500 g, 3.34 mmol) and DMAP (0.817 g, 6.68 mmol) in dry THF(10 mL), and the resulting mixture was stirred at 0° C. for 2 h. Thereaction was quenched by the addition of saturated aqueous ammoniumchloride solution (50 mL) and ethyl acetate (70 mL) was added. Theaqueous phase was separated and extracted with ethyl acetate (2×50 mL).The combined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified via column chromatography on silica gel (Biotage 50g column, gradient elution with 25-35% ethyl acetate in hexanes) toafford tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (0.660 g, 93%)as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.06 (d, J=6.74 Hz,3H), 1.40 (s, 9H), 2.11-2.25 (m, 2H), 2.36-2.45 (m, 1H), 2.68 (dd,J=14.51, 6.6 Hz, 1H), 3.25-3.36 (m, 1H), 3.93-4.06 (m, 1H), 4.42-4.48(m, 1H).

Step 2. (rac)-tert-butyl(cis)-4-hydroxy-2-methylpiperidine-1-carboxylate and (rac)-tert-butyl(trans)-4-hydroxy-2-methylpiperidine-1-carboxylate

Following the procedure found in Plettenburg, Oliver et. Al (PCT Int.Appl., 2007012421), sodium borohydride (213 mg, 5.6 mmol) was addedportion-wise to a solution of tert-butyl2-methyl-4-oxopiperidine-1-carboxylate (1.0 g, 4.7 mmol) in ethanol (10mL). The mixture was stirred at room temperature for 2 h. The solutionwas concentrated in vacuo and then partitioned between water (40 mL) andethyl acetate (40 mL). The aqueous layer was extracted twice with ethylacetate (40 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated invacuo. The residue was purified via column chromatography on silica gel(Biotage 50 g column, gradient elution with 40-50% ethyl acetate inhexanes) to afford (rac)-tert-butyl(cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (367 mg, 36%) and(rac)-tert-butyl (trans)-4-hydroxy-2-methylpiperidine-1-carboxylate (205mg, 20%) as white solids.

Step 3. (rac)-tert-butyl(cis)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

Triethylamine (0.49 mL, 3.49 mmol) was added to a 0° C. solution of(rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (250mg, 1.16 mmol) and methanesulfonyl chloride (0.14 mL, 1.74 mmol) indichloromethane (4.5 mL). The resulting mixture was warmed to roomtemperature and stirred overnight. The reaction was quenched by theaddition of saturated aqueous sodium bicarbonate (10 mL) anddichloromethane (10 mL) was added. The organic layer was separated andwashed with 1M aqueous citric acid (10 mL) and brine (10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified via column chromatography on silica gel (Biotage 50g column, gradient elution with 20-30% ethyl acetate in hexanes) toafford (rac)-tert-butyl(cis)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (315 mg,92%) as a colorless oil that slowly solidified to a white solid uponstanding. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17 (d, J=7.04 Hz, 3H), 1.38(s, 9H), 1.63-1.76 (m, 1H), 1.85-1.90 (m, 3H), 2.96-3.06 (m, 1H), 3.18(s, 3H), 3.72-3.78 (m, 1H), 4.16-4.24 (m, 1H), 4.93-4.98 (m, 1H).

Step 4. methyl(S)-6-(1-((2S,4R)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateand methyl(S)-6-(1-((2R,4S)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

(rac)-tert-Butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (55.9mg, 0.190 mmol) was added to a solution of (S)-methyl5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(50.0 mg, 0.146 mmol) and cesium carbonate (76 mg, 0.234 mmol) in DMF(1.0 mL), and the reaction mixture was heated to 100° C. and allowed tostir overnight. The mixture was cooled to room temperature, diluted withwater, and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with water (2×25 mL) and brine (25 mL), dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified via column chromatography on silica gel (Biotage 25g column, gradient elution with 20-30% ethyl acetate in hexanes) toafford a 1:1 mixture of methyl(S)-6-(1-((2S,4R)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateand methyl(S)-6-(1-((2R,4S)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(54.2 mg, 69%) as a colorless oil. MS (ESI, pos. ion) m/z 539 [M+H]⁺.

Step 5. methyl(S)-5-cyclobutoxy-2-methyl-6-(1-((2S,4R)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylateand methyl(S)-5-cyclobutoxy-2-methyl-6-(1-((2R,4S)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

Hydrogen chloride (4.0 N in 1,4-dioxane, 0.126 mL, 0.503 mmol) was addedto a solution containing a 1:1 mixture of methyl(S)-6-(1-((2S,4R)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateand methyl(S)-6-(1-((2R,4S)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate(54.2 mg, 0.101 mmol) in 1,4-dioxane (1.0 mL), and the reaction mixturestirred at room temperature for 3 h. The solution was concentrated undera stream of nitrogen, diluted with saturated aqueous sodium bicarbonatesolution (1.0 mL) and extracted with ethyl acetate (3×1.0 mL). Thecombined organic layers were added directly to a plug of silica gel, andthe product was eluted with 30% ethyl acetate in methanol to afford a1:1 mixture of methyl(S)-5-cyclobutoxy-2-methyl-6-(1-((2S,4R)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylateand methyl(S)-5-cyclobutoxy-2-methyl-6-(1-((2R,4S)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(18.1 mg, 41%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.81(d, J=6.74 Hz, 3H), 1.05 (d, J=6.74 Hz, 3H), 1.22-1.43 (m, 3H),1.48-1.65 (m, 2H), 1.81-2.22 (m, 8H), 2.34-2.43 (m, 1H), 2.72-2.87 (m,2H), 2.90-3.00 (m, 1H), 3.10-3.17 (m, 1H), 3.66 (s, 3H), 4.05-4.12 (m,1H), 4.40-4.52 (m, 1H), 7.21 (d, J=8.79 Hz, 1H), 7.30 (d, J=9.38 Hz,1H), 7.78 (s, 1H), 8.08 (s, 1H). MS (ESI, pos. ion) m/z 439 [M+H]⁺.

The following example was made according to the procedure describedabove for Example 107:

methyl(S)-5-cyclobutoxy-2-methyl-6-(1-((2S,4S)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-376) and methyl(S)-5-cyclobutoxy-2-methyl-6-(1-((2R,4R)-2-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate(I-377)

¹H NMR (300 MHz, DMSO-d6) δ ppm 0.80 (d, J=6.45 Hz, 3H), 1.05 (d, J=6.74Hz, 3H), 1.22-1.43 (m, 3H), 1.48-1.75 (m, 2H), 1.90-2.13 (m, 8H),2.34-2.45 (m, 1H), 2.58-2.70 (m, 2H), 2.76-2.86 (m, 1H), 2.99-3.05 (m,1H), 3.66 (s, 3H), 4.02-4.12 (m, 1H), 4.15-4.26 4.36-4.48 (m, 1H), 7.20(d, J=8.79 Hz, 1H), 7.29 (d, J=9.38 Hz, 1H), 7.76 (s, 1H), 8.01 (s, 1H).MS (ESI, pos. ion) m/z 439 [M+H]+.

Example 108 Library Protocol A

A half-dram vial was charged with(S)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol A (0.2 M inN,N-dimethylacetamide, 150 μL, 30 μmol) and potassium tert-butoxide (1 Min THF, 36 μL, 36 μmol), and the mixture was shaken for 5 seconds. Alkylhalide B (0.2 M in N,N-dimethylacetamide, 180 μL, 36 mol) was added, andthe system was sealed and shaken at 80° C. for 14 h. Ethyl acetate (0.7mL) and 1 N sodium hydroxide in brine (0.5 mL) were added and themixture was shaken. The organic layer was separated and the aqueousphase was extracted with ethyl acetate (1.0 mL). The combined organicphases were concentrated and the residue was dissolved in anhydrous1,4-dioxane (100 μL). Aryl boronic ester C (0.2 M in 1,4-dioxane, 270μL, 54 mol), potassium carbonate (1 M aqueous solution, 90 μL, 90 mol),and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.02 M in 1,2-dichloroethane, 150 μL, 3 mol)were added, and the mixture was sealed and shaken at 80° C. for 14 h.Ethyl acetate (0.5 mL) and 1 N sodium hydroxide in brine (0.4 mL) wereadded and the mixture was shaken. The organic layer was separated andthe aqueous phase was extracted with ethyl acetate (1.0 mL). Thecombined organic phases were concentrated to afford the crude product.This material was purified by mass triggered preparatory HPLC. Theproduct-containing fractions were combined and concentrated in a Genevacto afford the desired product.

The following compounds in Table 1 were synthesized according to theabove protocol:

TABLE 1 HPLC LC-MS RT Compounds Structure MW [M + 1]+ (min) I-378

398.46 399 0.82 I-379

408.46 409 1.05 I-380

448.54 449 0.91 I-381

392.46 393 1.21 I-382

432.54 433 1.04 I-383

382.46 383 0.95 I-384

367.45 368 1.12 I-385

393.53 394 1.75 I-386

382.51 383 0.78 I-387

353.47 354 1.47 I-388

353.47 354 1.41 I-389

365.48 366 1.50 I-390

365.48 366 1.49 I-391

368.44 369 0.89 I-392

379.50 380 1.63 I-393

401.51 402 1.57 I-394

367.49 368 1.60 I-395

395.50 396 1.23 I-396

379.50 380 1.57 I-397

350.42 351 1.19 I-398

369.47 370 1.23 I-399

402.50 403 1.05 I-400

409.53 410 1.30 I-401

396.49 397 0.97 I-402

407.56 408 1.89 I-403

402.50 403 1.19 I-404

325.41 326 1.22 I-405

405.50 406 1.16 I-406

408.52 409 1.17 I-407

419.54 420 1.18 I-408

385.51 386 1.26 I-409

431.55 432 1.20 I-410

397.52 398 1.28 I-411

369.47 370 1.11 I-412

408.55 409 0.91 I-413

475.60 476 1.07 I-414

441.57 442 1.13 I-415

413.52 414 0.98 I-416

452.60 453 0.84 I-417

462.57 463 0.82 I-418

428.53 429 0.86 I-419

439.56 440 0.67 I-420

433.57 434 1.29 I-421

399.54 400 1.39 I-422

371.48 372 1.20 I-423

410.56 411 0.98 I-424

459.61 460 1.42 I-425

425.57 426 1.52 I-426

397.52 398 1.33 I-427

436.00 437 1.08 I-428

488.60 489 0.90 I-429

454.57 455 0.95 I-430

426.52 427 0.84 I-431

465.60 466 0.75 I-432

474.58 475 0.84 I-433

440.54 441 0.88 I-434

412.49 413 0.79 I-435

451.57 452 0.70 I-436

512.64 513 0.97 I-437

478.61 479 1.01 I-438

450.55 451 0.89 I-439

489.64 490 0.77 I-440

398.51 399 0.66 I-441

435.54 436 1.43 I-442

401.51 402 1.51 I-443

373.45 374 1.33 I-444

447.55 448 1.46 I-445

413.52 414 1.52 I-446

385.46 386 1.33 I-447

424.55 425 1.10 I-448

491.60 492 1.30 I-449

457.57 458 1.36 I-450

429.52 430 1.21 I-451

468.60 469 1.04 I-452

478.56 479 1.02 I-453

444.53 445 1.06 I-454

455.56 456 0.86 I-455

449.57 450 1.54 I-456

415.53 416 1.64 I-457

387.48 388 1.45 I-458

426.56 427 1.18 I-459

475.60 476 1.67 I-460

441.57 442 1.78 I-461

413.52 414 1.58 I-462

452.60 453 1.28 I-463

504.60 505 1.11 I-464

470.57 471 1.16 I-465

442.52 443 1.03 I-466

481.60 482 0.93 I-467

490.58 491 1.03 I-468

456.54 457 1.07 I-469

428.49 429 0.98 I-470

467.57 468 0.88 I-471

528.64 529 1.18 I-472

494.61 495 1.22 I-473

466.55 467 1.10 I-474

505.63 506 0.96 I-475

476.59 477 0.87 I-476

442.56 443 0.89 I-476

414.51 415 0.82 I-477

453.59 454 0.70 I-478

406.49 407.19 1.21 I-479

402.50 403.19 0.98 I-481

442.52 443.20 1.41 I-482

401.52 402.23 1.47 I-483

444.55 445.24 1.02 I-484

415.55 416.26 1.57 I-485

458.57 459.25 1.10 I-486

410.56 411.30 1.09 I-487

453.58 454.32 0.79 I-488

436.55 437.30 1.42 I-489

479.58 480.35 0.99 I-490

416.54 417.25 1.48 I-491

459.56 460.21 1.06 I-492

401.52 402.23 1.49 I-493

444.55 445.23 1.04 I-494

416.54 417.27 1.43 I-495

459.56 460.27 1.02 I-496

436.55 437.30 1.40 I-497

479.58 480.33 0.98 I-498

442.57 443.26 1.53 I-499

485.60 486.30 1.09 I-500

442.57 443.25 1.64 I-501

485.60 486.32 1.17 I-502

430.56 431.26 1.57 I-503

473.59 474.29 1.12 I-504

363.46 364.16 2.19 I-505

362.47 363.20 1.97 I-506

396.49 397.13 1.10 I-506

384.48 385.16 1.10 I-507

435.57 436.25 1.60 I-508

483.63 484.21 1.51 I-509

455.57 456.22 1.51

Example 109 Library Protocol B

A half-dram vial was charged with(S)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol A (0.2 M inacetonitrile, 200 μL, 40 mol) and aryl halide B (0.4 M in acetonitrile,200 μL, 80 mol). Cesium carbonate (66 mg, 200 mol) was added, and thesystem was sealed and shaken at 80° C. for 14 h. Ethyl acetate (0.7 mL)and 1 N sodium hydroxide in brine (0.5 mL) were added and the mixturewas shaken. The organic layer was separated and the aqueous phase wasextracted with ethyl acetate (1.0 mL). The combined organic phases wereconcentrated and the residue was dissolved in anhydrous 1,4-dioxane (100μL). Pyrazole boronic ester C (0.2 M in 1,4-dioxane, 360 μL, 72 mol) andpotassium carbonate (1 M aqueous solution, 120 μL, 120 mol) were added,and the reaction was moved to a glove box.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.02 M in 1,2-dichloroethane, 200 μL, 4 mol) wasadded under a nitrogen atmosphere, and the mixture was sealed and shakenat 80° C. for 14 h. Ethyl acetate (0.5 mL) and 1 N sodium hydroxide inbrine (0.4 mL) were added and the mixture was shaken. The organic layerwas separated and the aqueous phase was extracted with ethyl acetate(1.0 mL). The combined organic phases were concentrated and the residuewas dissolved in anhydrous 1,4-dioxane (200 μL). HCl (4 M in1,4-dioxane, 100 μL) was added, and the system was sealed and shaken at50° C. for 2 h. The mixture was concentrated and dissolved in ethylacetate (500 μL). The solution was transferred to a silica-based, cationexchange column (SCX 0.5 g) and washed with ethyl acetate/methanol (3:1,3 mL) (to elute waste) followed by ammonia (2 M in methanol, 3 mL) (toelute product). The ammonia solution was concentrated to afford thecrude product. This material was purified by mass triggered preparatoryHPLC. The product-containing fractions were combined and concentrated ina Genevac to afford the desired product.

The following compounds in Table 2 were synthesized according to theabove protocol:

TABLE 2 HPLC LC-MS RT Compounds Structure MW [M+1]+ (min) I-511

450.52 451.25 0.78 I-512

499.54 500.27 1.08 I-513

432.53 433.27 0.74 I-514

500.53 501.27 0.99 I-515

500.53 501.29 1.00 I-516

517.63 518.28 0.82 I-517

472.59 473.32 0.91 I-518

472.59 473.33 0.92 I-519

500.53 501.29 0.98 I-520

474.57 475.31 0.73 I-521

517.53 518.31 1.12 I-522

489.58 490.29 0.94 I-523

474.57 475.29 0.74 I-524

515.54 516.28 1.24 I-525

448.53 449.22 0.92 I-526

448.53 449.25 0.96 I-527

515.54 516.27 1.20 I-528

516.53 517.29 1.14 I-529

516.53 517.29 1.16 I-530

533.63 534.34 1.00 I-531

488.59 489.29 1.08 I-532

488.59 489.31 1.08 I-533

466.52 467.25 1.00 I-534

516.53 517.27 1.15 I-535

462.55 463.28 0.98 I-536

533.53 534.31 1.28 I-537

505.58 506.26 1.10 I-538

490.56 491.28 0.89 I-539

525.58 526.17 1.15 I-540

482.59 483.15 1.00 I-541

525.58 526.16 1.18

Example 110 Library Protocol C

A half-dram vial was charged with(S)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol A (0.2 M inacetonitrile, 150 μL, 30 μmol) and aryl halide B (0.4 M in acetonitrile,150 μL, 60 μmol). Cesium carbonate (50 mg, 150 μmol) was added, and thesystem was sealed and shaken at 80° C. for 14 h. Ethyl acetate (0.7 mL)and 1 N sodium hydroxide in brine (0.5 mL) were added and the mixturewas shaken. The organic layer was separated and the aqueous phase wasextracted with ethyl acetate (1.0 mL). The combined organic phases wereconcentrated and the residue was dissolved in anhydrous 1,4-dioxane (100μL). Aryl boronic ester C (0.2 M in 1,4-dioxane, 270 μL, 54 μmol) andpotassium carbonate (1 M aqueous solution, 90 μL, 90 μmol) were added,and the reaction was transferred to a glove box.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.02 M in 1,2-dichloroethane, 150 μL, 3 μmol)was then added under a nitrogen atmosphere, and the mixture was sealedand shaken at 80° C. for 14 h. Ethyl acetate (0.5 mL) and brine (0.5 mL)were added and the mixture was shaken. The organic layer was separatedand the aqueous phase was extracted with ethyl acetate (1.0 mL). Thecombined organic phases were concentrated and the residue was purifiedby mass triggered preparatory HPLC. The product-containing fractionswere combined and concentrated in a Genevac to afford the desiredproduct.

The following compounds in Table 3 were synthesized according to theabove protocol:

TABLE 3 HPLC LC-MS RT Compounds IUPAC Structure MW [M+1]+ (min) I-542

461.45 462.26 1.11 I-543

411.44 412.21 0.91 I-544

421.50 422.26 0.94 I-545

435.53 436.27 1.07 I-546

423.47 424.24 0.89 I-547

433.51 434.28 1.02 I-548

496.56 497.20 1.33 I-549

455.50 456.17 1.18 I-550

473.52 474.18 0.98 I-551

439.49 440.20 1.03 I-552

439.49 440.19 1.08 I-553

496.56 497.21 1.24 I-554

538.54 539.27 1.53 I-555

504.51 505.26 1.59 I-556

476.46 477.21 1.46 I-557

472.47 473.22 1.75 I-558

471.53 472.22 1.18 I-559

437.50 438.26 1.22 I-560

409.45 410.19 1.09 I-561

405.46 406.20 1.38 I-562

538.54 539.24 1.52 I-563

504.51 505.26 1.58 I-564

476.46 477.23 1.43 I-565

472.47 473.21 1.76 I-566

495.55 496.22 1.31 I-567

461.52 462.24 1.34 I-568

433.47 434.21 1.22 I-569

429.48 430.19 1.50 I-570

511.60 512.26 1.32 I-571

477.57 478.26 1.36 I-572

449.51 450.22 1.24 I-573

445.52 446.26 1.53 I-574

489.52 490.20 1.23 I-575

455.49 456.24 1.27 I-576

427.44 428.21 1.14 I-577

423.45 424.18 1.43 I-578

539.53 540.24 1.41 I-579

505.50 506.26 1.46 I-580

477.44 478.21 1.33 I-581

473.46 474.22 1.63 I-582

485.56 486.25 1.20 I-583

451.53 452.27 1.23 I-584

423.47 424.21 1.11 I-585

419.49 420.21 1.40 I-586

513.57 514.26 1.04 I-587

447.50 448.22 1.18 I-588

556.53 557.25 1.59 I-589

522.50 523.31 1.66 I-590

494.45 495.23 1.52 I-591

490.46 491.25 1.82 I-592

465.53 466.15 1.69 I-593

436.49 437.10 1.21

Example 111 Library Protocol D

A half-dram vial was charged with aryl boronic acid B (0.2 M in1,4-dioxane, 500 μL, 100 μmol) and copper (II) acetate (0.2 M in water,260 μL, 52 μmol). The mixture was concentrated and molecular sieves (50mg) were added. (S)-6-Bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol A(0.2 M in 1,2-dichloroethane, 200 μL, 40 μmol) and pyridine (0.5 M in1,2-dichloroethane, 400 μL, 200 μmol) were added, and the system wassealed and shaken at 80° C. for 14 h. Ethyl acetate (0.7 mL) andsaturated aqueous ammonium chloride solution (0.5 mL) were added and themixture was shaken. The organic layer was separated and the aqueousphase was extracted with ethyl acetate (1.0 mL). The combined organicphases were concentrated and the residue was dissolved in anhydrous1,4-dioxane (100 μL). Pyrazole boronic ester C (0.2 M in 1,4-dioxane,400 μL, 80 mol) and potassium carbonate (1 M aqueous solution, 120 μL,120 mol) were added, and the reaction was transferred to a glove box.[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.02 M in 1,2-dichloroethane, 200 μL, 4 mol) wasthen added under a nitrogen atmosphere, and the mixture was sealed andshaken at 80° C. for 14 h. Ethyl acetate (0.5 mL) and 1 N sodiumhydroxide in brine (0.4 mL) were added and the mixture was shaken. Theorganic layer was separated and the aqueous phase was extracted withethyl acetate (1.0 mL). The combined organic phases were concentratedand the residue was dissolved in anhydrous 1,4-dioxane (200 μL). (NOTE:For examples lacking a Boc-protected intermediate, the following acidhydrolysis step and SCX purification were omitted). HCl (4 M in1,4-dioxane, 100 μL) was added, and the system was sealed and shaken at50° C. for 2 h. The mixture was concentrated and dissolved in ethylacetate (500 μL). The solution was transferred to a silica-based, cationexchange column (SCX 0.5 g) and washed with ethyl acetate/methanol (3:1,3 mL) (to elute waste) followed by ammonia (2 M in methanol, 3 mL) (toelute product). The ammonia solution was concentrated to afford thecrude product. This material was purified by mass triggered preparatoryHPLC. The product-containing fractions were combined and concentrated ina Genevac to afford the desired product.

The following compounds in Table 4 were synthesized according to theabove protocol:

TABLE 4 HPLC LC-MS RT Compounds IUPAC Structure MW [M+1]+ (min) I-594

387.48 388.14 1.55 I-595

458.56 459.17 1.23 I-596

471.56 472.11 1.16

Example 112 Library Protocol E

A reaction vial was charged with6-bromo-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.2 M in1,2-dichloroethane, 0.10 mL, 0.02 mmol), N,N-diisopropylethyl amine(10.5 μL, 0.06 mmol), and an acid chloride or chloroformate (A) (0.5 Min 1,2-dichloroethane, 0.05 mL, 0.025 mmol), and the mixture was shakenat 50° C. for 2 h. Ethyl acetate and water were added and the mixturewas shaken. The organic layer was separated and the aqueous phase wasextracted with ethyl acetate. The combined organic phases wereconcentrated and the residue was dissolved in anhydrous 1,4-dioxane (100μL).1-Cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.2 M in 1,4-dioxane, 0.10 mL, 0.02 mmol) and sodium bicarbonate (1 Maqueous solution, 0.06 mL, 0.06 mmol) were added, and the reaction wastransferred to a glove box.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.02 M in 1,2-dichloroethane, 0.05 mL, 0.001mmol) was then added under a nitrogen atmosphere, and the mixture wassealed and shaken at 80° C. for 18 h. Ethyl acetate and water were addedand the mixture was shaken. The organic layer was separated and theaqueous phase was extracted with ethyl acetate. The combined organicphases were concentrated to afford the crude product. This material waspurified by mass triggered preparatory HPLC. The product-containingfractions were combined and concentrated in a Genevac to afford thedesired product.

The following compounds in Table 5 were synthesized according to theabove protocol:

TABLE 5 HPLC LC-MS RT Compounds IUPAC Structure MW [M+1]+ (min) I-597

387.48 388 1.55 I-598

413.52 414 1.76 I-599

403.48 404 1.81

Example 113 Library Protocol F

A reaction vial was charged with(S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone(0.2 M in N,N-dimethylacetamide, 0.100 mL, 0.02 mmol) and (R)- or(S)-tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate A (0.2 M inN,N-dimethylacetamide, 0.12 mL, 0.024 mmol). Potassium tert-butoxide (1M in THF, 0.024 mL, 0.024 mmol) was added, and the system was sealed andshaken at 80° C. overnight. Ethyl acetate and 1 N sodium hydroxide inbrine were added and the mixture was shaken. The organic layer wasseparated and the aqueous phase was extracted with ethyl acetate. Thecombined organic phases were concentrated and the residue was dissolvedin anhydrous 1,4-dioxane (100 μL). Pyrazole boronic ester B (0.2 M in1,4-dioxane, 0.15 mL, 0.030 mmol) and potassium carbonate (1 M aqueoussolution, 0.060 mL, 0.060 mmol) were added, and the reaction wastransferred to a glove box.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.02 M in 1,2-dichloroethane, 0.10 mL, 2.0 mol)was then added under a nitrogen atmosphere, and the mixture was sealedand shaken at 80° C. for 4 h. Ethyl acetate and 1 N sodium hydroxide inbrine were added and the mixture was shaken. The organic layer wasseparated and the aqueous phase was extracted with ethyl acetate (1.0mL). The combined organic phases were concentrated to afford the crudeproduct. The residue was dissolved in in 1,2-dichloroethane (0.1 mL),trifluoroacetic acid (0.1 mL, 1.3 mmol) was added, and the mixturestirred at rt for 2 h. The reaction mixture was concentrated and theresidue was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate solution. The aqueous layer was separated andextracted with ethyl acetate, and the combined organic layers wereconcentrated under a stream of nitrogen and vacuum. The crude productwas purified by mass-triggered preparatory HPLC. The product-containingfractions were combined and concentrated in a Genevac to afford thedesired product.

The following compounds in Table 6 were synthesized according to theabove protocol:

TABLE 6 HPLC LC-MS RT Compounds IUPAC Structure MW [M+1]+ (min) I-600

410.52 411 0.73 I-601

410.52 411 0.73 I-602

394.52 395 0.83 I-603

394.52 395 0.83 I-604

426.56 427 0.75

Example 114 Library Protocol G

A 1.5-mL reaction vial was charged with(S)-1-(5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.2 Msolution in N,N-dimethylacetamide, 0.1 mL g, 0.02 mmol) and potassiumtert-butoxide (1 M in THF, 0.024 mL, 0.024 mmol). The aryl halide (A)(0.2 M solution in N,N-dimethylacetamide, 0.12 mL, 0.024 mmol) was thenadded, and the reaction was heated to 80° C. on a heater shakerovernight. The reaction was diluted with ethyl acetate and washed with 1N aqueous sodium hydroxide solution. The aqueous layer was separated andwashed with ethyl acetate and the combined organic layers wereconcentrated under a stream of nitrogen and vacuum. The crude productwas purified by mass triggered preparatory HPLC. The product-containingfractions were combined and concentrated in a Genevac to afford thedesired product.

The following examples in Table 7 were made according to the aboveprotocol:

TABLE 7 HPLC LC-MS RT Compounds IUPAC Structure MW [M+1]+ (min) I-605

247.34 248 1.60 I-606

290.36 291 0.90 I-607

287.40 288 1.95

Example 119 AlphaScreen Binding Assay

The binding of Example compounds to BRD4 Bromodomain 1 and BRD4Bromodomain 2 was assessed using 384-well AlphaScreen assay technology.His-epitope tagged BRD4 BD1₄₄₋₁₆₈ and BRD4 BD2₃₃₃₋₄₆₀ were cloned,expressed, and purified to homogeneity. BRD4 BD1 and BRD4 BD2 bindingand inhibition was assessed by monitoring the engagement of biotinylatedHistone H4 (1-21) K5/8/12/16 tetra-acetylated peptide with the targetsusing the AlphaScreen technology (PerkinElmer). Specifically, in a384-well black or white flat bottom plate, BRD4 BD1 (50 nM final) orBRD4 BD2 (100 nM final) was combined with peptide (50 nM final for BD1or 100 nM final for BD2) in 50 mM HEPES (pH 7.3), 100 mM NaCl, 0.1%(w/v) BSA, and 0.01% (w/v) Triton X-100 either in the presence of DMSO(final 1.25% DMSO) or compound dilution series in DMSO. Alphastreptavidin donor beads and Nickel-chelate acceptor beads were added toa final concentration of 10 μg/ml each. After a minimum of 1 hourequilibration, plates were read on a BMG PHERAstar FS multi-label reader(BMG LabTech). The half maximal inhibitory concentration (IC₅₀) valueswere calculated using IDBS Activity Base software with a four parameterlogistic curve fit by the equation y=A+((B−A)/(1+((C/x)̂D))), wherein Adenotes the bottom plateau of the curve, B denotes the top plateau ofthe curve, C denotes the x value at the middle of the curve, D denotesthe slope factor, x denotes the original known x values, and y denotesthe original known y values. Data was fitted using the LevenburgMarquardt algorithm.

Table 8 below provides activity of representative compounds according toInhibition of BRD4 BD1. The compounds are grouped in four categories;inhibition at a concentration <0.1 μM; inhibition at a concentrationbetween 0.1 μM and 1 μM; inhibition at a concentration between 1 μM and10 μM; inhibition at a concentration >10 μM.

TABLE 8 Exemplary compounds arranged according to inhibition of BRD4BD1. Compounds with BRD4 BD1 IC₅₀ <0.1 μM I-48 I-104 I-311 I-312 I-361I-385 I-415 I-416 I-423 I-426 I-427 I-447 Compounds with BRD4 BD1 0.1 ≧IC 50 ≦ 1 μM I-1 I-7 I-8 I-17 I-22 I-23 I-24 I-31 I-39 I-42 I-43 I-44I-49 I-50 I-51 I-53 I-54 I-55 I-57 I-61 I-62 I-67 I-68 I-71 I-72 I-73I-77 I-78 I-79 I-80 I-81 I-84 I-86 I-88 I-89 I-91 I-92 I-93 I-96 I-97I-98 I-99 I-100 I-101 I-102 I-103 I-105 I-107 I-108 I-109 I-110 I-113I-124 I-124 I-127 I-128 I-129 I-130 I-132 I-133 I-134 I-135 I-136 I-137I-138 I-139 I-140 I-141 I-142 I-143 I-144 I-145 I-146 I-148 I-149 I-150I-151 I-152 I-153 I-155 I-156 I-157 I-158 I-159 I-160 I-161 I-162 I-163I-164 I-165 I-166 I-167 I-168 I-169 I-170 I-171 I-172 I-173 I-174 I-175I-176 I-177 I-178 I-179 I-180 I-181 I-182 I-183 I-184 I-185 I-186 I-187I-188 I-189 I-190 I-191 I-192 I-193 I-194 I-195 I-196 I-197 I-198 I-199I-200 I-201 I-202 I-203 I-204 I-205 I-206 I-207 I-209 I-210 I-211 I-213I-216 I-217 I-219 I-221 I-222 I-223 I-224 I-225 I-226 I-228 I-229 I-230I-232 I-233 I-236 I-240 I-241 I-242 I-243 I-245 I-246 I-247 I-248 I-249I-250 I-255 I-256 I-258 I-259 I-260 I-261 I-263 I-263 I-264 I-265 I-266I-267 I-268 I-269 I-270 I-271 I-272 I-273 I-274 I-275 I-276 I-278 I-281I-282 I-283 I-285 I-287 I-288 I-290 I-291 I-292 I-293 I-294 I-295 I-296I-297 I-298 I-302 I-303 I-307 I-310 I-313 I-315 I-316 I-317 I-318 I-320I-321 I-322 I-329 I-330 I-331 I-332 I-333 I-335 I-336 I-341 I-343 I-360I-362 I-363 I-364 I-365 I-366 I-367 I-368 I-369 (I-370 + I-371)*(I-374 + I-375)* (I-376 + I-377)* I-382 I-387 I-388 I-389 I-390 I-392I-394 I-395 I-396 I-398 I-400 I-401 I-402 I-407 I-408 I-409 I-411 I-412I-413 I-420 I-422 I-424 I-425 I-431 I-444 I-446 I-449 I-458 I-459 I-461I-462 I-466 I-506 I-506 I-507 I-508 I-509 I-511 I-512 I-518 I-519 I-521I-540 I-542 I-543 I-545 I-546 I-547 I-550 I-551 I-552 I-553 I-585 I-592I-593 I-594 I-595 I-598 I-600 I-602 I-603 Compounds with BRD4 BD1 1 ≧IC₅₀ ≦ 10 μM I-2 I-3 I-4 I-5 I-6 I-10 I-11 I-13 I-14 I-15 I-16 I-18 I-19I-25 I-26 I-27 I-28 I-29 I-30 I-32 I-33 I-35 I-36 I-37 I-38 I-40 I-41I-46 I-47 I-56 I-59 I-63 I-65 I-69 I-70 I-74 I-82 I-83 I-85 I-87 I-90I-94 I-95 I-106 I-111 I-114 I-115 I-117 I-118 I-119 I-120 I-121 I-123I-125 I-126 I-131 I-147 I-154 I-212 I-214 I-215 I-218 I-220 I-227 I-231I-234 I-235 I-238 I-239 I-251 I-252 I-254 I-257 I-277 I-279 I-280 I-284I-286 I-289 I-299 I-301 I-305 I-309 I-314 I-319 I-323 I-328 I-334 I-337I-338 I-339 I-340 I-348 I-349 I-350 I-351 I-352 I-359 (I-372 + I-373)*I-378 I-379 I-380 I-381 I-383 I-384 I-386 I-391 I-393 I-397 I-399 I-403I-404 I-405 I-406 I-410 I-414 I-417 I-418 I-419 I-421 I-428 I-429 I-430I-432 I-433 I-434 I-435 I-436 I-437 I-438 I-439 I-440 I-441 I-442 I-443I-445 I-448 I-450 I-451 I-452 I-453 I-454 I-455 I-456 I-457 I-460 I-463I-464 I-465 I-467 I-468 I-469 I-470 I-471 I-472 I-473 I-474 I-475 I-476I-476 I-477 I-478 I-479 I-482 I-483 I-484 I-485 I-486 I-487 I-488 I-490I-491 I-492 I-493 I-494 I-495 I-496 I-497 I-498 I-499 I-500 I-501 I-502I-503 I-504 I-505 I-513 I-514 I-515 I-516 I-517 I-520 I-522 I-523 I-524I-525 I-526 I-527 I-528 I-529 I-531 I-532 I-533 I-534 I-535 I-536 I-537I-538 I-539 I-541 I-544 I-548 I-549 I-554 I-555 I-556 I-557 I-558 I-559I-560 I-561 I-562 I-563 I-564 I-565 I-566 I-567 I-568 I-569 I-570 I-571I-572 I-573 I-574 I-575 I-576 I-577 I-578 I-579 I-580 I-581 I-582 I-583I-584 I-586 I-587 I-588 I-589 I-590 I-591 I-596 I-597 I-599 I-601 I-604Compounds with BRD4 BD 1 IC₅₀ ≧10 μM I-9 I-12 I-20 I-21 I-34 I-45 I-52I-58 I-60 I-64 I-75 I-112 I-116 I-244 I-245 I-253 I-300 I-304 I-306I-308 I-324 I-325 I-326 I-327 I-343 I-344 I-345 I-346 I-347 I-353 I-354I-355 I-356 I-357 I-358 I-481 I-489 I-530 I-605 I-606 I-607 *refers toracemic mixtures of enantiomers

Table 9 provides the compounds arranged according to Inhibition of BRD4BD2. The compounds are grouped in three groups; IC₅₀<0.05 μM;0.05≧IC₅₀≦0.5 μM; and IC₅₀>0.5 μM.

TABLE 9 Exemplary compounds arranged according to inhibition of BRD4 BD2Compounds with BRD4 BD2 IC₅₀ <0.05 μM I-11 I-22 I-24 I-27 I-31 I-36 I-39I-44 I-48 I-49 I-50 I-51 I-53 I-62 I-67 I-68 I-77 I-80 I-83 I-84 I-86I-88 I-92 I-99 I-100 I-101 I-102 I-104 I-108 I-111 I-132 I-133 I-134I-135 I-136 I-137 I-138 I-139 I-140 I-141 I-144 I-145 I-148 I-149 I-150I-151 I-152 I-153 I-157 I-158 I-159 I-160 I-161 I-162 I-163 I-164 I-166I-167 I-168 I-169 I-170 I-185 I-188 I-189 I-191 I-200 I-201 I-210 I-211I-214 I-216 I-217 I-218 I-224 I-225 I-227 I-245 I-246 I-249 I-255 I-256I-257 I-258 I-259 I-263 I-263 I-268 I-270 I-282 I-283 I-285 I-287 I-288I-351 I-361 I-362 I-363 I-364 I-365 I-366 I-385 I-387 I-389 I-390 I-393I-396 I-401 I-407 I-408 I-409 I-410 I-411 I-412 I-415 I-416 I-420 I-422I-423 I-424 I-426 I-427 I-442 I-443 I-444 I-445 I-447 I-458 I-461 I-462I-479 I-506 I-511 I-521 I-545 I-546 I-547 I-550 I-551 I-552 I-553 I-563I-592 I-593 I-594 Compounds with BRD4 BD2 0.05 ≧ IC₅₀ ≦ 0.5 μM I-1 I-2I-3 I-4 I-5 I-7 I-8 I-10 I-13 I-14 I-15 I-16 I-17 I-18 I-19 I-21 I-23I-25 I-26 I-29 I-30 I-32 I-34 I-35 I-37 I-38 I-40 I-41 I-42 I-43 I-46I-47 I-61 I-63 I-65 I-78 I-79 I-81 I-82 I-85 I-87 I-89 I-90 I-91 I-93I-107 I-112 I-113 I-114 I-115 I-116 I-117 I-119 I-121 I-142 I-143 I-146I-147 I-155 I-190 I-209 I-212 I-213 I-215 I-226 I-247 I-251 I-254 I-277I-284 I-286 I-289 I-352 I-356 I-359 I-378 I-379 I-380 I-381 I-382 I-383I-384 I-388 I-392 I-395 I-397 I-398 I-399 I-400 I-402 I-403 I-404 I-405I-406 I-413 I-414 I-417 I-418 I-419 I-421 I-425 I-428 I-429 I-430 I-431I-432 I-433 I-434 I-435 I-436 I-437 I-438 I-439 I-440 I-441 I-446 I-448I-449 I-450 I-451 I-452 I-453 I-454 I-455 I-456 I-457 I-459 I-460 I-463I-464 I-465 I-466 I-467 I-468 I-469 I-470 I-471 I-472 I-473 I-474 I-475I-476 I-476 I-477 I-478 I-484 I-486 I-488 I-490 I-491 I-492 I-494 I-496I-497 I-498 I-499 I-500 I-501 I-502 I-503 I-505 I-506 I-512 I-513 I-514I-515 I-516 I-517 I-518 I-519 I-520 I-522 I-523 I-524 I-525 I-526 I-527I-528 I-529 I-531 I-532 I-533 I-534 I-535 I-536 I-537 I-538 I-539 I-540I-541 I-542 I-543 I-544 I-548 I-549 I-554 I-555 I-556 I-557 I-558 I-559I-560 I-561 I-562 I-564 I-565 I-566 I-567 I-568 I-569 I-570 I-571 I-572I-573 I-574 I-575 I-577 I-578 I-579 I-580 I-581 I-582 I-583 I-584 I-585I-586 I-587 I-588 I-589 I-590 I-591 I-595 I-596 I-597 I-598 I-599 I-600I-601 I-602 I-603 Compounds with BRD4 BD2 IC₅₀ ≧0.5 μM I-6 I-9 I-12 I-20I-28 I-33 I-45 I-52 I-58 I-59 I-60 I-64 I-118 I-120 I-252 I-253 I-353I-354 I-355 I-357 I-358 I-386 I-391 I-481 I-482 I-483 I-485 I-487 I-489I-493 I-495 I-504 I-530 I-576 I-604 I-605 I-606 I-607

Example 120 Oncology Cell Growth Assay

The impact of Example compounds on cancer cell proliferation wasdetermined using the acute myelocytic leukemia (AML) cell line MV4-11(ATCC) in a 3-day proliferation assay. MV4-11 cells were maintained inRPMI 1640 media supplemented with 10% FBS at 37° C. and an atmosphere of5% CO₂. For compound testing, compound dilutions series were prepared inDMSO via a 3-fold serial dilution from 2 mM to 0.001 mM in 384-wellwhite flat bottom plates. The final compound concentrations in the wellswere 10, 3.3, 1.1, 0.37, 0.12, 0.041, 0.013 and 0.0045 M. MV4-11 cellswere plated at a density of 3000 cells/well in final volume of 50 μlculture media and incubated for 72 hours. The amounts of viable cellswere determined using the CellTiter-Glo Luminescent Cell Viability Assaykit (Promega) according to the manufacturer suggested protocol.Luminescent signal from the CellTiter-Glo assay was read on an EnVisionmultilabel plate reader (PerkinElmer). Values for the concentration thatinhibited cell growth by 50% (gIC₅₀) between the DMSO control andbackground control (no cells) were determined using IDBS Activity Basesoftware with a four parameter logistic curve fit by the equationy=A+((B−A)/(1+((C/x)̂D))), wherein A denotes the bottom plateau of thecurve, B denotes the top plateau of the curve, C denotes the x value atthe middle of the curve, D denotes the slope factor, x denotes theoriginal known x values, and y denotes the original known y values. Datawas fitted using the Levenburg Marquardt algorithm.

Table 10 provides the compounds arranged according to inhibition ofproliferation of MV411 cell line. The compounds are grouped in threegroups; IC₅₀<0.5 μM; 0.5 μM≧IC₅₀≦1.0 μM; and IC₅₀>1.0 μM.

TABLE 10 Exemplary compounds arranged according to inhibition of MV411Compounds with MV 411 IC₅₀ <0.5 μM I-1 I-7 I-8 I-22 I-30 I-48 I-51 I-53I-54 I-55 I-57 I-61 I-62 I-67 I-68 I-72 I-77 I-78 I-80 I-81 I-83 I-84I-86 I-88 I-89 I-91 I-92 I-93 I-94 I-95 I-96 I-97 I-98 I-99 I-100 I-101I-102 I-103 I-104 I-105 I-107 I-108 I-109 I-110 I-113 I-127 I-129 I-130I-132 I-133 I-134 I-135 I-136 I-137 I-138 I-139 I-140 I-141 I-142 I-143I-144 I-145 I-146 I-147 I-148 I-149 I-150 I-151 I-152 I-153 I-154 I-156I-157 I-158 I-159 I-160 I-162 I-163 I-164 I-165 I-166 I-167 I-168 I-169I-170 I-171 I-172 I-173 I-174 I-175 I-176 I-177 I-178 I-179 I-180 I-181I-182 I-183 I-184 I-185 I-186 I-187 I-188 I-189 I-190 I-191 I-192 I-193I-194 I-195 I-196 I-197 I-198 I-199 I-200 I-201 I-202 I-203 I-204 I-205I-206 I-207 I-209 I-210 I-211 I-212 I-213 I-214 I-216 I-217 I-218 I-219I-220 I-221 I-222 I-223 I-224 I-225 I-226 I-227 I-228 I-229 I-230 I-231I-232 I-233 I-234 I-235 I-236 I-238 I-239 I-240 I-241 I-242 I-243 I-245I-246 I-247 I-248 I-249 I-250 I-255 I-256 I-257 I-258 I-259 I-260 I-261I-263 I-264 I-265 I-266 I-267 I-268 I-269 I-270 I-271 I-272 I-273 I-274I-275 I-276 I-278 I-280 I-282 I-283 I-285 I-286 I-287 I-288 I-290 I-291I-292 I-293 I-294 I-295 I-296 I-297 I-298 I-302 I-303 I-305 I-307 I-309I-310 I-311 I-312 I-315 I-316 I-318 I-319 I-320 I-321 I-322 I-323 I-328I-329 I-330 I-331 I-332 I-333 I-334 I-335 I-336 I-343 I-348 I-351 I-359I-360 I-361 I-362 I-363 I-364 I-365 I-366 I-367 I-368 I-369 (I-374 +I-375)* (I-376 + I-377)* I-385 I-387 I-389 I-390 I-392 I-394 I-396 I-400I-401 I-407 I-408 I-409 I-410 I-411 I-412 I-413 I-415 I-416 I-420 I-422I-423 I-424 I-425 I-426 I-427 I-442 I-443 I-444 I-445 I-446 I-447 I-449I-458 I-486 I-506 I-508 I-509 I-511 I-512 I-513 I-514 I-517 I-518 I-519I-521 I-524 I-525 I-526 I-527 I-528 I-529 I-531 I-533 I-535 I-539 I-540I-541 I-542 I-543 I-545 I-547 I-548 I-550 I-551 I-552 I-553 I-568 I-569I-572 I-577 I-583 I-585 I-592 I-593 I-594 I-595 I-596 I-597 I-598 I-599Compounds with MV411 0.5 μM ≧ IC₅₀ ≦ 1.0 μM I-564 I-546 I-215 I-584I-352 I-39 I-506 I-82 I-71 I-128 I-590 I-46 I-121 I-431 I-402 I-119I-284 I-124 I-56 I-131 I-591 I-50 I-516 I-549 I-36 I-561 I-124 I-567I-556 I-522 I-589 I-573 I-536 I-515 I-574 I-388 I-560 I-31 I-462 I-341I-398 I-70 I-289 I-537 I-281 I-562 I-575 I-73 I-580 I-317 I-565 I-382(I-370 + I-371)* I-587 I-44 I-69 I-17 I-74 I-263 I-532 I-534 I-507 I-35I-338 I-13 I-571 I-461 I-23 I-395 I-299 I-559 I-602 Compounds with MV411IC₅₀ >1.0 μM I-11 I-14 I-19 I-20 I-24 I-29 I-34 I-42 I-43 I-49 I-60 I-63I-64 I-75 I-106 I-114 I-115 I-116 I-117 I-118 I-120 I-123 I-125 I-126I-155 I-161 I-244 I-245 I-251 I-252 I-253 I-254 I-279 I-300 I-301 I-304I-306 I-308 I-313 I-314 I-324 I-325 I-326 I-327 I-337 I-339 I-340 I-343I-344 I-345 I-346 I-347 I-349 I-350 I-353 I-354 I-355 I-356 I-357 I-358(I-372 + I-373)* I-459 I-466 I-479 I-487 I-491 I-501 I-504 I-505 I-520I-523 I-530 I-538 I-554 I-555 I-557 I-558 I-563 I-566 I-570 I-576 I-578I-579 I-581 I-582 I-586 I-588 I-600 I-603 *refers to racemic mixtures ofenantiomers

It is expected and indicated in the literature, that all BET familyinhibitors have some activity for all BET bromodomains.

EQUIVALENTS

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound of Formula I:

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,prodrug, isomer, or tautomer thereof, wherein: W is O, S, C(O), or CHR³;X is N or CR⁴; Y is N or CR⁶; Z is N or CR⁷; R¹ is hydrogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl; R² is hydrogen or NR^(a)R^(b); R³ ishydrogen, halogen, hydroxyl, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R⁴ ishydrogen, —(CH₂)_(n)R^(d), —O(CH₂)_(n)R^(d), —N(CH₂)_(n)R^(d),—O(CH₂)_(n)C(O)R^(d), or —O(CH₂)_(n)S(O)₂R^(d); R⁵ and R⁶ are eachindependently hydrogen, halogen, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—(C₁-C₆)-alkylene-aryl, —(C₁-C₆)-alkylene-heteroaryl,—(C₁-C₆)-alkylene-heterocycloalkyl, —(CR^(a)R^(b))_(n)OR^(c),—(CR^(a)R^(b))_(n)R^(c), —O(CR^(a)R^(b))_(n)NR^(a)R^(b), —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)S(O)₂R^(b), or R^(c), wherein said alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, and heteroaryl are optionally substituted withone or more substituents independently selected from R^(a), R^(b), andR^(c); R⁷ is hydrogen or halogen; R⁸ is R^(a), —OR^(a), —NR^(a), orheterocycloalkyl; R^(a) and R^(b) are each independently hydrogen,halogen, C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl, wherein C₁-C₆alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted withone or more R^(e); R^(c) is —NH₂, OH, —NH(C₁-C₆ alkyl),—O(CH₂)_(n)NR^(a)R^(b), —NH(C₁-C₆ alkoxy), —(CH₂)_(n)R^(a),—(CH₂)_(n)OR^(a), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),—(CH₂)_(n)S(O)₂CH₃, —S(O)₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)—S(O)₂R^(b),—NHC(O)R^(a), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, halo, cyano, or oxo, wherein C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R^(e); or two adjacent R^(c) can combinewith the carbons to which they are attached to form a carbocycle orheterocycle; R^(d) is hydrogen, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, whereinsaid alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl areoptionally substituted with one or more substituents independentlyselected from R^(a), R^(b), and R^(c); R^(e) is hydrogen, halogen, OH,C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, oxo, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C₁-C₆ alkoxy, or S(O)₂(C₁-C₆ alkyl); and n is 0, 1, or
 2. 2.The compound of claim 1, wherein X is CR⁴ and Y and Z are CH.
 3. Thecompound of claim 2, wherein W is CHR³.
 4. The compound of claim 1,having the Formula II

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,prodrug, isomer, or tautomer thereof, wherein: W is O, C(O), or CHR³; Aris aryl or heteroaryl; R² is hydrogen or NR^(a)R^(b); R³ is hydrogen,hydroxy, or halo; R⁴ hydrogen, —O(CH₂)_(n)R^(d), —O(CH₂)_(n)C(O)R^(d),or —O(CH₂)_(n)S(O)₂R^(d); R⁷ is hydrogen or halo; R⁸ is R^(a), —OR^(a),or heterocycloalkyl; R^(a) and R^(b) are independently hydrogen, C₁-C₆alkyl, heterocycloalkyl, or cycloalkyl; R^(c) is R^(a),—(CH₂)_(n)OR^(a), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b)—S(O)₂R^(a),halo, or oxo; and n is 0, 1, or
 2. 5. The compound of claim 4, wherein Wis CHR³.
 6. The compound of claim 4, wherein Ar is pyrazole or phenyl.7. The compound of claim 1, having the Formula III

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,prodrug, isomer, or tautomer thereof, wherein: Ar is pyrazolyl orphenyl; R⁴ is hydrogen, —O(CH₂)_(n)R^(d), —O(CH₂)_(n)C(O)R^(d), or—O(CH₂)_(n)S(O)₂R^(d); R⁸ is methyl, methoxy, or cyclopropyl; R^(a) andR^(b) are independently hydrogen or C₁-C₆ alkyl; R^(c) is—(CH₂)_(n)R^(a), —(CH₂)_(n)OR^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —(CH₂)_(n)S(O)₂CH₃, —S(O)₂R^(a), —S(O)₂NR^(a)R^(b),C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, cycloalkyl, heterocycloalkyl, halo,cyano, or oxo; R^(d) is hydrogen, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, whereinsaid alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl areoptionally substituted with one or more substituents independentlyselected from R^(a), R^(b), and R^(c); and n is 0, 1, or
 2. 8. Thecompound of claim 7, wherein Ar is pyrazole and R^(c) is cycloalkyl orheterocycloalkyl.
 9. The compound of claim 8, wherein R^(c) iscyclopropyl.
 10. The compound of claim 7, wherein Ar is phenyl, R^(c) is—(CH₂)_(n)S(O)₂CH₃.
 11. The compound of claim 1, having the Formula IV

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate,prodrug, isomer, or tautomer thereof, wherein: R⁴ is —O(CH₂)_(n)R^(d),—O(CH₂)_(n)C(O)R^(d), or —O(CH₂)_(n)S(O)₂R^(d); R⁸ is alkyl, cycloalkyl,O-alkyl, or O-cycloalkyl R^(a) and R^(b) are independently hydrogen orC₁-C₆ alkyl; R^(c) is —(CH₂)_(n)R^(a), —(CH₂)_(n)OR^(a), —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(a)R^(b)—S(O)₂R^(a), —S(O)₂NR^(a)R^(b), C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, halo, cyano, or oxo; R^(d) is hydrogen, NH(C₁-C₆alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl,aryl, and heteroaryl are optionally substituted with one or moresubstituents independently selected from R^(a), R^(b), and R^(c); and nis 0, 1, or
 2. 12. The compound of claim 11, wherein R^(c) iscycloalkyl, or heterocycloalkyl.
 13. The compound of claim 12, whereinR⁴ is —O(CH₂)_(n)R^(d).
 14. The compound of claim 13, wherein R^(d) isaryl, heteroaryl, or cycloalkyl.
 15. The compound of claim 1 selectedfrom the group consisting of: methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-{octahydrocyclopenta[c]pyrrol-5-yl}-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3,3-difluorocyclobutoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-(azetidin-3-ylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-(3-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoroethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoropropoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(4-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(1,3-difluoropropan-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(3,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-2-methylpropanamide;(2S)-1-cyclopropanecarbonyl-5-(2-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-1-cyclopropanecarbonyl-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;1-(2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)pyrrolidin-2-one;(2S)-1-cyclopropanecarbonyl-5-(4-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(morpholin-4-yl)ethan-1-one;methyl(2S)-5-(2-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;2-(2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-1λ⁶,2-thiazolidine-1,1-dione;methyl(2S)-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methanesulfonamide;methyl(2S)-5-(4-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylmethanesulfonamide;methyl(2S)-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[2-(oxetan-3-yl)ethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(2,2-difluorocyclopropyl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;3-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyridin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(3-fluorooxetan-3-yl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3,3-difluorocyclobutoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(azetidin-3-ylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-imidazol-4-yl)-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-({1-[(tert-butoxy)carbonyl]azetidin-3-yl}oxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ⁶-thietan-3-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ⁶-thian-3-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2R)-2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-2-fluoroacetamide;(2S)-2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-2-fluoroacetamide;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(3-fluorooxetan-3-yl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-2,2-difluoroacetamide;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-2-methylpropoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;methyl(2S)-5-[(dimethylcarbamoyl)methoxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N-ethylacetamide;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoroethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N-cyclopropyl-N-methylacetamide;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(azetidin-1-yl)ethan-1-one;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(piperidin-1-yl)ethan-1-one;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoroethoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoroethoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,2-difluoropropoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(carbamoyldifluoromethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(1,3-difluoropropan-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-2-methylpropoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(1-carbamoyl-1-methylethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(R)-carbamoyl(fluoro)methoxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(S)-carbamoyl(fluoro)methoxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(ethylcarbamoyl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-{[cyclopropyl(methyl)carbamoyl]methoxy}-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[2-(azetidin-1-yl)-2-oxoethoxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[2-oxo-2-(piperidin-1-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[2-(morpholin-4-yl)-2-oxoethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[2-(1,1-dioxo-1λ⁶,2-thiazolidin-2-yl)ethoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(sulfamoylmethoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(dimethylsulfamoyl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[2-(oxetan-3-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(2,2-difluorocyclopropyl)methoxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(quinazolin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(1,3-benzoxazol-2-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(1,3-benzoxazol-2-yloxy)-2-methyl-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(pyrimidin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carboxamide;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{1H-pyrazolo[3,4-d]pyrimidin-6-yloxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1,3-thiazol-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carbonitrile;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(3-chloropyridin-2-yl)oxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyridin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(4,6-dimethylpyrimidin-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;6-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridazine-3-carbonitrile;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-propoxy-1,2,3,4-tetrahydroquinoline;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinoline;1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-(1-{octahydrocyclopenta[c]pyrrol-5-yl}-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[6-(4-methanesulfonylphenyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-(2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl)ethan-1-one;1-[(2S)-5-cyclopropoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(5-methanesulfonylpyridin-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;N-{6-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]pyridin-3-yl}methanesulfonamide;2-{[(2S)-1-acetyl-6-(5-methanesulfonylpyridin-2-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-6-(1,3-benzoxazol-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-5-propoxy-6-{pyrazolo[1,5-a]pyridin-2-yl}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-{imidazo[1,2-a]pyridin-2-yl}-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1,3-benzothiazol-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1H-1,3-benzodiazol-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,3,4-tetrahydroquinoline;5-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1,3,4-thiadiazol-2-amine;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-(4-chloro-2-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(2-cyano-4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(2-chloro-4-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-cyano-2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;methyl(2S)-5-(2-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2-cyanophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2-cyano-3-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;4-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(3-chloropyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carbonitrile;1-[(2S)-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-(4-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(3-cyanopyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(2-cyano-3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(3-chloro-2-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;2-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;2-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-6-fluorobenzonitrile;4-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-3-fluorobenzonitrile;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(3-chloro-4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;4-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzamide;1-[(2S)-5-(2-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(2-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-carbamoylphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(3-cyano-4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(3-chloro-4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-(2-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-(4-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;4-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-(3-chloro-4-fluorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(3,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(3-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(3,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-(3,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(3-chlorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(3-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline;(2S)-5-(3-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(3,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(3,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-(3,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-5-(3,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;5-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1,3,4-thiadiazol-2-amine;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;4-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzamide;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-imidazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;methyl(2S)-6-[1-(1,1-dioxo-1λ⁶-thian-3-yl)-1H-pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(1,1-dioxo-1λ⁶-thietan-3-yl)-1H-pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(4-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;3-{4-[(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thietane-1,1-dione;3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thietane-1,1-dione;1-[(2S)-5-(2-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-cyanophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(2-chlorophenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-carbamoylphenoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;4-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;methyl(2S)-5-(4-chloro-2-cyanophenoxy)-2-methyl-6-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[1-(propan-2-yl)azetidin-3-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-2-methyl-6-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-(1-{2-methyl-octahydrocyclopenta[c]pyrrol-5-yl}-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-{2-methyl-octahydrocyclopenta[c]pyrrol-5-yl}-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(1-ethylazetidin-3-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[1-(propan-2-yl)azetidin-3-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(1-ethylazetidin-3-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(isoquinolin-1-yloxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-(2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-5-(2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(2,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-5-(2,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(2,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2,4-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-5-(2,3-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(2,3-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-(2,3-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2,3-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(2,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(2,5-difluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-(2,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-5-(2,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;1-[(2S)-5-(3,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(2,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one1-[(2S)-5-{[(E)-2-chloroethenyl]oxy}-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-{1H,2H,3H-pyrazolo[1,5-a]imidazol-7-yl}-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-methanesulfonyl-1H,2H,3H-pyrazolo[1,5-a]imidazol-7-yl}-2-methyl-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-cyclobutoxy-6-[2-(4-hydroxypiperidin-4-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-[2-(4-fluoropiperidin-4-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(3-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(5-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(5-chloropyridin-2-yl)oxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(7H-purin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-cyclobutoxy-6-[1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-6-[1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-[1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-6-[1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione;3-{4-[(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(2-oxopiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(2-oxopiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-{1-[(2S)-2-methylazetidin-3-yl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-{1-[(2S)-2-methylazetidin-3-yl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydroquinoline-1-carboxylate;N-{4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1-cyclopropyl-1H-pyrazol-5-yl}methanesulfonamide;N-{4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1-cyclopropyl-1H-pyrazol-5-yl}acetamide;methyl(2S)-5-cyclobutoxy-6-[1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[2-(piperidin-4-yl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-methyl-2-(piperidin-4-yl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;2-{[(2S)-1-acetyl-2-methyl-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N-methylacetamide;1-[(2S)-2-methyl-5-(1,2-oxazol-5-ylmethoxy)-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;N-(2-{[(2S)-1-acetyl-2-methyl-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)methanesulfonamide;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1,2-oxazol-5-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;N-(2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)methanesulfonamide;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N-methylacetamide;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(oxetan-3-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(cyclopentylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[2-(dimethylamino)ethoxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(propan-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(cyclopropylmethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}acetamide;1-[(2S)-5-(cyclobutylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(benzyloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(3-methyloxetan-3-yl)methoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(cyclopentyloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}acetonitrile;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-methoxyethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyridin-3-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-5-(cyclohexylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(1,3-thiazol-5-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-cyclobutoxy-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-cyclobutoxy-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-cyclobutoxy-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-cyclobutoxy-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-5-(oxan-4-ylmethoxy)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;2-{[(2S)-1-acetyl-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-5-(2-methylpropoxy)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(cyclopentylmethoxy)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(cyclopentylmethoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(pyrrolidin-1-yl)ethan-1-one;2-{[(2S)-1-acetyl-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(pyrrolidin-1-yl)ethan-1-one;2-{[(2S)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(pyrrolidin-1-yl)ethan-1-one;2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-1-(pyrrolidin-1-yl)ethan-1-one;(5R)-5-({[(2S)-1-acetyl-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methyl)pyrrolidin-2-one;(5R)-5-({[(2S)-1-acetyl-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methyl)pyrrolidin-2-one;(5R)-5-({[(2S)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methyl)pyrrolidin-2-one;(5R)-5-({[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methyl)pyrrolidin-2-one;N-(2-{[(2S)-1-acetyl-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-N-methylmethanesulfonamide;N-(2-{[(2S)-1-acetyl-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-N-methylmethanesulfonamide;N-(2-{[(2S)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-N-methylmethanesulfonamide;N-(2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}ethyl)-N-methylmethanesulfonamide;1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-[(3S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-5-(oxan-4-ylmethoxy)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(dimethylcarbamoyl)methoxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(dimethylcarbamoyl)methoxy]-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(dimethylcarbamoyl)methoxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-5-(2-methylpropoxy)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(cyclopentylmethoxy)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(cyclopentylmethoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-5-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-5-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-(N-methylmethanesulfonamido)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-(N-methylmethanesulfonamido)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-[2-(N-methylmethanesulfonamido)ethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-5-[2-(N-methylmethanesulfonamido)ethoxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-[(3S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-[(3S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl (2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-[(3S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl (2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-[(3S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(5-methyl-1,3-oxazol-2-yl)methoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyridin-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(1,3-benzoxazol-2-ylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(4-methanesulfonylphenyl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-(4-methanesulfonylphenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-6-[4-(ethanesulfonyl)phenyl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-[4-(ethanesulfonyl)phenyl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-6-{4-[2-(dimethylamino)ethoxy]phenyl}-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-{4-[2-(dimethylamino)ethoxy]phenyl}-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-2-methyl-6-[3-(morpholine-4-carbonyl)phenyl]-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-2-methyl-6-[3-(morpholine-4-carbonyl)phenyl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;N-{3-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]phenyl}methanesulfonamide;2-{[(2S)-1-acetyl-6-(3-methanesulfonamidophenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-6-(3-methanesulfonylphenyl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-(3-methanesulfonylphenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;N-{4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]phenyl}methanesulfonamide;2-{[(2S)-1-acetyl-6-(4-methanesulfonamidophenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-2-methyl-6-[4-(morpholine-4-carbonyl)phenyl]-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-2-methyl-6-[4-(morpholine-4-carbonyl)phenyl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;2-{4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]phenyl}-1λ⁶,2-thiazolidine-1,1-dione;2-{[(2S)-1-acetyl-6-[4-(1,1-dioxo-1λ⁶,2-thiazolidin-2-yl)phenyl]-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-6-(1-methanesulfonyl-2,3-dihydro-1H-indol-5-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-(1-methanesulfonyl-2,3-dihydro-1H-indol-5-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;N-{4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]phenyl}-N-methylmethanesulfonamide;2-{[(2S)-1-acetyl-2-methyl-6-[4-(N-methylmethanesulfonamido)phenyl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-6-(1-benzofuran-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1H-indol-2-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;3-{4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione;3-{4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thietane-1,1-dione;1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyrimidin-2-yloxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-5-{[6-(morpholin-4-yl)pyrimidin-4-yl]oxy}-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(6-cyclopropylpyrimidin-4-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carboxamide;1-[(2S)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl6-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carboxylate;6-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carboxamide;methyl(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyrimidin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-5-{[6-(morpholin-4-yl)pyrimidin-4-yl]oxy}-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(6-cyclopropylpyrimidin-4-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-{[5-(methoxycarbonyl)pyridin-2-yl]oxy}-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(5-carbamoylpyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline;2-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}pyridine-3-carbonitrile;(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline;1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(4,6-dimethylpyrimidin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(propan-2-yl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-5-[(5-methoxypyrimidin-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-(1-methanesulfonyl-2,3-dihydro-1H-indol-5-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-(4-methanesulfonylphenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{4-[(2S)-1-acetyl-5-[(5-fluoropyrimidin-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]phenyl}-1λ⁶,2-thiazolidine-1,1-dione;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(pyrazin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(3-cyanopyridin-2-yl)oxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(3-cyanopyridin-2-yl)oxy]-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(3-cyanopyridin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(3-cyanopyridin-2-yl)oxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(5-cyclopropylpyrimidin-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(5-fluoropyrimidin-2-yl)oxy]-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-[(5-fluoropyrimidin-2-yl)oxy]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(5-methylpyrimidin-2-yl)oxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(3-carbamoylpyridin-2-yl)oxy]-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-[(3-carbamoylpyridin-2-yl)oxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-6-[1-(2-methanesulfonylethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;4-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylbenzamide;methyl(2S)-5-(3-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-cyclopropanecarbonyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline;methyl6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-2-methyl-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-5-[(3R)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-6-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-5-[(3S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(3R)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(3S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-5-[(3S)-pyrrolidin-3-ylmethoxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}-N,N-dimethylacetamide;1-[(2S)-5-(cyclopentylmethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-({1-[(1E)-prop-1-en-1-yl]-1H-1,3-benzodiazol-2-yl}oxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-({1-[(1Z)-prop-1-en-1-yl]-1H-1,3-benzodiazol-2-yl}oxy)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-methyl-2-(piperazin-1-yl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[2-(piperazin-1-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-[2-(3-hydroxyazetidin-1-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1,2-oxazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-6-(1,2-oxazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-8-fluoro-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-1-cyclopropanecarbonyl-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;methyl(2S)-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-cyclobutoxy-7,8-difluoro-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-cyclobutoxy-6-(1-cyclopropyl-1H-pyrazol-4-yl)-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(2H-1,2,3-triazol-2-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(2H-1,2,3-triazol-2-yl)-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-5-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[5-(piperidin-4-yl)-1H-imidazol-2-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-5-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[5-(piperidin-4-yl)-1H-imidazol-2-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-8-fluoro-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-1-cyclopropanecarbonyl-2-methyl-5-[(6-methylpyridin-2-yl)oxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-[(2,6-dimethylpyridin-3-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-[(2,6-dimethylpyridin-4-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-[(6-chloropyridin-2-yl)oxy]-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyridin-2-yloxy)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-[(6-fluoropyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;methyl(2S)-2-methyl-5-[(6-methylpyridin-2-yl)oxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-(pyridin-2-yloxy)-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-2-methyl-5-[(6-methylpyridin-2-yl)oxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-1-cyclopropanecarbonyl-2-methyl-6-[4-(morpholin-4-yl)-1H-pyrazol-1-yl]-5-phenoxy-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[4-(piperazin-1-yl)-1H-pyrazol-1-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[4-(piperidin-4-yl)-1H-pyrazol-1-yl]-1,2,3,4-tetrahydroquinoline;methyl(2S)-2-methyl-6-[4-(morpholin-4-yl)-1H-pyrazol-1-yl]-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-5-phenoxy-6-[4-(piperazin-1-yl)-1H-pyrazol-1-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-6-carbonitrile;(2S)-1-cyclopropanecarbonyl-6-ethynyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(prop-1-yn-1-yl)-1,2,3,4-tetrahydroquinoline;methyl(2S)-6-cyano-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-ethynyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-[2-(azetidin-3-yl)-1,3-thiazol-4-yl]-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-[2-(3-fluoroazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-[2-(3-hydroxyazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-[2-(3-methoxyazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-6-(2-carbamoyl-1,3-thiazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[2-(methylcarbamoyl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-(2-acetamido-1,3-thiazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-6-cyclopropyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline;methyl(2S)-6-cyclopropyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-8-fluoro-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;methyl(2S)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-1-cyclopropanecarbonyl-5-(3-methoxyphenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(2,5-difluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(3,4-difluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;2-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;(2S)-1-cyclopropanecarbonyl-5-(3-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(2-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-[(6-methoxypyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-[(6-methoxypyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-5-[(6-methoxypyridin-2-yl)oxy]-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ⁶-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;4-{4-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ⁶-thiane-1,1-dione;1-[(2S)-6-(1-acetylpiperidin-4-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-6-(1-methanesulfonylpiperidin-4-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;tert-butyl4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate;1-[(2S)-2-methyl-6-(piperidin-4-yl)-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]-N-ethylpiperidine-1-carboxamide;methyl4-[(2S)-1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl]piperidine-1-carboxylate;1-[(2S)-6-(1-ethylpiperidin-4-yl)-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-5-(phenylamino)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl (2S)-5-cyclobutoxy-6-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl (2S)-5-cyclobutoxy-6-{1-[(3S,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl (2S)-5-(4-fluorophenoxy)-6-{1-[(3S,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl (2S)-5-(4-fluorophenoxy)-6-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-6-{1-[(3R,4S)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-{1-[(3R,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(4-fluorophenoxy)-6-{1-[(3R,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(2-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(2-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-cyclobutoxy-6-[5-fluoro-1-(piperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-6-{1-[(3R*,4S*)-4-fluoropyrrolidin-3-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;and(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-[(3R*,4S*)-4-fluoropiperidin-3-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline.16. The compound of claim 15 selected from the group consisting: methyl(2S)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5-propoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-2-methylpropoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;2-{[(2S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;2-{[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;1-[(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(4-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-(2-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-(4-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(2-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(3-chlorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(3-cyanophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;1-[(2S)-5-(2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;1-[(2S)-5-[(5-chloropyridin-2-yl)oxy]-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;methyl(2S)-5-(2-cyano-3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-(3-chloro-4-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-5-cyclobutoxy-2-methyl-6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl (2S)-5-cyclobutoxy-6-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one;(2S)-5-(4-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;4-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;2-{[(2S)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy}benzonitrile;methyl(2S)-6-[1-(1,1-dioxo-11⁶-thietan-3-yl)-1H-pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-5-(3-chloro-4-fluorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-6-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(2-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-(2-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(3-fluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(3,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-(3,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-5-(2,4-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-2-methyl-6-(1-methyl-1H-imidazol-4-yl)-5-phenoxy-1,2,3,4-tetrahydroquinoline;(2S)-5-(3-chlorophenoxy)-1-cyclopropanecarbonyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(2,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-(3,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;(2S)-1-cyclopropanecarbonyl-5-(3,5-difluorophenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-6-{1-[(3S,4R)-3-fluoropiperidin-4-yl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-5-(2-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-(3-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;3-{4-[(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-11⁶-thietane-1,1-dione;3-{4-[(2S)-1-cyclopropanecarbonyl-5-(4-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-11⁶-thiane-1,1-dione;(2S)-1-cyclopropanecarbonyl-5-(4-methoxyphenoxy)-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;(2S)-1-cyclopropanecarbonyl-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline;methyl(2S)-5-cyclobutoxy-8-fluoro-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;methyl(2S)-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate;and1-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one.17. A pharmaceutical composition comprising the compound of claim 1 anda pharmaceutically acceptable carrier.
 18. The pharmaceuticalcomposition of claim 17, further comprising therapeutically effectiveamounts of one or more additional therapeutic agents.
 19. Thepharmaceutical composition of claim 18, wherein said additionaltherapeutic agents are selected from the group consisting of cytotoxicagent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan,camptostar, topotecan, paclitaxel, docetaxel, the epothilones,tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide,SCH 66336, tipifarnib, R115777, L778,123, BMS 214662, C225, GLEEVEC®,Intron®, Peg-Intron®, aromatase combinations, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, leucovirin, oxaliplatin(ELOXATIN®), Pentostatine, Vinblastine, Vincristine, Vindesine,Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin,Mithramycin™, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Rituximab, C225, Campath, leucovorin, dexamethasone, bicalutamide,carboplatin, chlorambucil, cisplatin, letrozole, megestrol, andvalrubicin.
 20. A method of inhibiting one or more of BET-familybromodomains in a patient comprising administering to the patient inneed thereof an effective amount of the compound of claim
 1. 21. Amethod of inhibiting one or more of BET-family bromodomains in a patientcomprising administering to the patient in need thereof an effectiveamount of the pharmaceutical composition of claim
 17. 22. A method oftreating, preventing, inhibiting, or eliminating a disease or disorderassociated with the activity of one or more BET-family bromodomains in apatient comprising administering to said patient in need thereof atherapeutically effective amount of the compound of claim
 1. 23. Themethod of claim 22, wherein said disease or disorder is selected fromthe group consisting of cancer, inflammatory disorders, irritable bowelsyndrome, inflammatory bowel disease, rheumatoid arthritis, obesity, anddiabetes.
 24. A male contraceptive comprising a therapeuticallyeffective amount of at least one compound of claim
 1. 25. A malecontraceptive comprising a therapeutically effective amount of at leastone compound of claim
 15. 26. A compound of any one of claims 1-16 foruse in the manufacture of a medicament for treating a disease associatedwith inhibiting one or more of BET-family bromodomains.
 27. Use of acompound of any one of claims 1-16 in the treatment of a diseaseassociated with inhibiting one or more of BET-family bromodomains.